Image-based brachytherapy for cervical cancer

Cervical cancer is the third most common cancer in women worldwide; definitive radiation therapy and concurrent chemotherapy is the accepted standard of care for patients with node positive or locally advanced tumors > 4 cm. Brachytherapy is an important part of definitive radiotherapy shown to improve overall survival. While results for two-dimensional X-ray based brachytherapy have been good in terms of local control especially for early stage disease, unexplained toxicities and treatment failures remain. Improvements in brachytherapy planning have more recently paved the way for three-dimensional image-based brachytherapy with volumetric optimization which increases tumor control, reduces toxicity, and helps predict outcomes.Advantages of image-based brachytherapy include:improved tumor coverage(especially for large volume disease), decreased dose to critical organs(especially for small cervix), confirmation of applicator placement, and accounting for sigmoid colon dose. A number of modalities for image-based brachytherapy have emerged including: magnetic resonance imaging(MRI),computed tomography(CT), CT-MRI hybrid, and ultrasound with respective benefits and outcomes data. Forpractical application of image-based brachytherapy the Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology Working Group and American Brachytherapy Society working group guideline serve as invaluable tools, additionally here-in we outline our institutional clinical integration of these guidelines. While the body of literature supporting image-based brachytherapy continues to evolve a number of uncertainties and challenges remain including: applicator reconstruction, increasing resource/cost demands, mobile four-dimensional targets and organs-at-risk, and accurate contouring of "grey zones" to avoid marginal miss. Ongoing studies, including the prospective EMBRACE(an international study of MRI-guided brachytherapy in locally advanced cervical cancer) trial, along with continued improvements in imaging, contouring, quality assurance, physics, and brachytherapy delivery promise to perpetuate the advancement of image-based brachytherapy to optimize outcomes for cervical cancer patients.

Californium-252 neutron brachytherapy combined with external pelvic radiotherapy plus concurrent chemotherapy for cervical cancer: a retrospective clinical study

Background:Cervical cancer is the sixth most common cancer in Chinese women.A standard treatment modal?ity for cervical cancer is the combination of surgery,chemotherapy,external?beam radiotherapy and intracavitary brachytherapy.The aim of this study was to retrospectively assess the long?term treatment outcomes of patients with cervical cancer who were treated with californium?252 neutron brachytherapy combined with external?beam radio?therapy plus concurrent chemotherapy.Methods:We retrospectively analyzed the medical records of 150 patients with primary stages IB?IVB cervical cancer who received neutron brachytherapy combined with external?beam radiotherapy concurrently with cisplatin chemo?therapy.All patients were followed up.Using an actuarial analysis,patient outcomes and treatment?related adverse effects were evaluated and compared.Results:The median overall survival(OS)was 33.2 months.The 3?year progression?free survival rates for patients with stages I–II,III,and IV diseases were 81.0%(68/84),65.0%(39/60),and 0%(0/6),respectively;the 3?year OS rates were 90.5%(76/84),85.0%(51/60),and 16.7%(1/6),respectively.Vaginal bleeding was controlled within the median time of4.0 days.One month after treatment,97.3%of patients achieved short?term local control.The local recurrence rates for patients with stages I–II,III,and IV disease were 4.8%(4/84),11.7%(7/60),and 33.3%(2/6),respectively,and the occurrence rates of distant metastasis were 16.7%(14/84),25.0%(15/60),and 100.0%(6/6),respectively.Cancer stage,tumor size,and lymph node metastasis were identified as prognostic risk factors,but only lymph node metastasis was found to be an independent prognostic factor.The most common adverse effects during treatment were grades 1 and 2 irradiation?related proctitis and radiocystitis.Conclusion:For patients with cervical cancer,neutron brachytherapy combined with external?beam radiotherapy plus concurrent chemotherapy produces a rapid response and greatly improves local control and long?term survival rates with tolerable adverse effects.

Dose-volume parameters and clinical outcome of CT-guided free-hand high-dose-rate interstitial brachytherapy for cervical cancer

Currently, image-based 3-dimentional (3D) planning brachytherapy allows for a better assessment of gross tumor volume (GTV) and the definition and delineation of target volume in cervix cancer. In this study, we investigated the feasibility of our novel computed tomography (CT)-guided free-hand high-dose- rate interstitial brachytherapy (HDRISBT) technique for cervical cancer by evaluating the dosimetry and preliminary clinical outcome of this approach. Dose-volume histogram (DVH) parameters were analyzed according to the Gynecological GEC-ESTRO Working Group recommendations for image-based 3D treatment in cervical cancer. Twenty cervical cancer patients who underwent CT-guided free-hand HDRISBT between March 2009 and June 2010 were studied. With a median of 5 (range, 4-7) implanted needles for each patient, the median dose of brachytherapy alone delivered to 90% of the target volume (D90 ) was 45 (range, 33-54) Gyα/β10 for high-risk clinical target volume (HR-CTV) and 30 (range, 20-36) Gyα/β10 for intermediate-risk clinical target volume (IR-CTV). The percentage of the CTV covered by the prescribed dose (V100 ) of HR-CTV with brachytherapy alone was 81.9%-99.2% (median, 96.7%). With an additional dose of external beam radiotherapy (EBRT), the median D90 was 94 (range, 83-104) Gyα/β10 for HR-CTV and 77 (range, 70 -87) Gyα/β10 for IR-CTV; the median dose delivered to 100% of the target volume (D100 ) was 75 (range, 66-84) Gyα/β10 for HR-CTV and 65 (range, 57-73) Gyα/β10 for IR-CTV. The minimum dose to the most irradiated 2 cc volume (D2cc ) was 73-96 (median, 83) Gyα/β3 for the bladder, 64-98 (median, 73) Gyα/β3 for the rectum, and 52-69 (median, 61) Gyα/β3 for the sigmoid colon. After a median follow-up of 15 months (range, 3 -24 months), two patients experienced local failure, and 1 showed internal iliac nodal metastasis. Despite the relatively small number of needles used, CT-guided HDRISBT for cervical cancer showed favorable DVH parameters and clinical outcome.

Knockdown of circular RNA (CircRNA)_001896 inhibits cervical cancer proliferation and stemness in vivo and in vitro

Objective:Previous studies indicated that aberrant circular RNA(circRNA)expression affects gene expression regulatory networks,leading to the aberrant activation of tumor pathways and promoting tumor cell growth.However,the expression,clinical significance,and effects on cell propagation,invasion,and dissemination of circRNA_001896 in cervical cancer(CC)tissues remain unclear.Methods:The Gene Expression Omnibus(GEO)datasets(GSE113696 and GSE102686)were used to examine differential circRNA expression in CC and adjacent tissues.The expression of circRNA_001896 was detected in 72 CC patients usingfluorescence quantitative PCR.Correlation analysis with clinical pathological features was performed through COX multivariate and univariate analysis.The effect of circRNA_001896 downregulation on CC cell propagation was examined using the cell counting kit-8(CCK-8)test,clonogenic,3D sphere formation,and in vivo tumorigenesis assays.Results:Intersection of the GSE113696 and GSE102686 datasets revealed an increased expression of four circRNAs,including circRNA_001896,in CC tissues.Fluorescence quantitative PCR confirmed circRNA_001896 as a circular RNA.High expression of circRNA_001896 was considerably associated with lymph node metastasis,International Federation of Gynecologists and Obstetricians(FIGO)stage,tumor diameter,and survival period in CC patients.Proportional hazards model(COX)univariate and multivariate analyses revealed that circRNA_001896 expressions are a distinct risk factor affecting CC patients’prognosis.Cellular functional experiments showed that downregulating circRNA_001896 substantially suppressed CC cell growth,colony formation,and 3D sphere-forming ability.In vivo,tumorigenesis analysis in nude mice demonstrated that downregulating circRNA_001896 remarkably reduced the in vivo proliferation capacity of CC cells.Conclusion:CircRNA_001896 is highly expressed in CC tissues and is substantially related to lymph node metastasis,FIGO stage,tumor size,and survival period in patients.Moreover,downregulating circRNA_001896 significantly inhibits both in vivo and in vitro propagation of CC cells.Therefore,circRNA_001896 might be used as a biomarker for targeted therapy in cervical cancer.

Image-Based Brachytherapy in Cervical Cancer: Review and Experiences in Faculty of Medicine, Chiang Mai University

Cervical cancer is the one of the most common cancer in female patients inThailand. Radiotherapy has the role for the treatment of cervical cancer by postoperative, radical and palliative treatments. For radical radiotherapy, the combination of external beam radiation therapy and brachytherapy will be used to increase the tumor dose to curative goal. With the new development of medical images (Computed tomography (CT), Magnetic Resonance Imaging (MRI) or Ultrasonography (US)), the treatment with brachytherapy will be developed from point-based to volume-based concepts. Many studies reported the benefit of image-based brachytherapy over conventional brachytherapy and clinical benefit of using image-based brachytherapy in the treatment of cervical cancer.

Subgroups of peripheral immune effector cells in cervical cancer patients are more sensitive to radiation therapy than chemotherapy

Background:CD8 positive T lymphocytes and natural killer(NK)cells in the peripheral blood of cervical cancer patients exhibit varying sensitivities to radiotherapy and chemotherapy.Methods:A total of 50 healthy peoples and 60 cervical cancer patients were recruited.The patients with cervical cancer were separated into two groups:radiation and chemotherapy,and blood sample were collected before and after treatment.Data on the proportion of CD8 positive T lymphocytes and NK cells were gathered for analytical evaluation.Results:Compared to healthy individuals,patients with cervical cancer exhibit a reduced proportion of CD8 positive T cells within their peripheral blood.And for patients with cervical cancer,radiation therapy has been found to be more effective than chemotherapy in increasing the proportion of CD8 positive T lymphocytes and NK cells.Conclusions:These results suggest that radiation therapy increases the levels of CD8 positive T lymphocytes and NK cells within the peripheral blood of patients with cervical cancer.The study hypothesis that the changes in the percentage of CD8 positive T lymphocytes may serve as a potential indicator for predicting treatment efficacy.

Attitudes and Practices Contributing to Vaginal Stenosis in Women with Cervical Cancer Following Brachytherapy at Cancer Diseases Hospital in Lusaka, Zambia. A Cross Sectional Study

Background: Vaginal stenosis is an important adverse effect of brachytherapy for cervicalcancer. This study aimed to determine attitudes and practices contributing to vaginal stenosis following brachytherapy at the Cancer Diseases Hospital in Lusaka—Zambia. Methods: An analytical cross-sectional study design was employed, where 163 respondents were randomly selected after meeting inclusion criteria. A researcher-administered questionnaire was used to collect data and SPSS version 25 was used for data analysis. Results: Out of the 163 women enrolled in this study, 42.3% had developed vaginal stenosis while 57.7% did not with age range 15 - 60+ years. 76% exhibited good practices to measures against vaginal stenosis while majority (93.9%) of the respondents demonstrated poor attitudes towards measures to prevent the condition. Women with poor practices versus good practices (OR = 1.07, CI = 0.52 - 2.21, p = 0.855), poor attitudes versus good attitudes (aOR = 1.28, CI = 0.29 - 5.71, p = 0.746) and those employed versus unemployed (aOR = 1.76, CI = 0.73 - 4.27, p = 0.210) had increased odds of vaginal stenosis. However, these increasing effects were not significant at 5% level of significance. Although length of brachytherapy showed no significant effect independently, the odds of having vaginal stenosis were over 2 times higher for women who had been on brachytherapy between 6 and 12 months compared to those on brachytherapy for less than 6 months (OR = 2.45, CI = 1.03 - 5.82, p = 0.042). Conclusions: Failure to practice recommended measures and poor attitudes towards therapy contributes to vaginal stenosis. Efforts should be channeled towards overcoming religious, traditional, cultural and personal impediments contributing to vaginal stenosis in women with cervical cancer receiving brachytherapy.

The Experience of Pain and Anxiety in Cervical Cancer Patients Undergoing Multiple Fraction High-Dose Rate Brachytherapy: A Prospective Observational Study

Purpose: To evaluate the anxiety and pain levels of cervical cancer patients undergoing intracavitary multifraction high-dose rate (HDR) brachytherapy, as part of a process to develop guidelines for quality patient-centered care. Methods: Cervical cancer patients (n = 31) undergoingmultiple fraction HDR brachytherapy treatment at the National Institute of Oncology in Rabat (Morocco) completed ratings of pain and anxiety intensity using 11-point verbal analog scales, at 6 key time points over 2 brachytherapy insertion procedures and 4 brachytherapy fractions. Women were evaluated for psychological status at baseline before starting the brachytherapy process using the Hospital Anxiety and Depression Scale (HADS). Scores were grouped as follows: 0 - 7 = normal, 8 - 10 = borderline, 11 - 21 = abnormal. Factors that could affect anxiety levels such as education level, relationship status, number of pregnancies and prior surgical history were documented. Results: Between July and August 2020, 31 women with a median age of 49.6 years were evaluated (range: 27 - 70). The HADS score identified depression in 5 patients (16.1%) and anxiety in 12 patients (38.7%). Throughout both treatment procedures, anticipatory anxiety was reported, with a maximum intensity in the operating room during spinal anesthesia (3.23 ± 1.7) and during applicator insertion (2.97 ± 2.4). Moderate-to-severe anxiety scores were reported in 25.8% and 22.6% of patients respectively. Level of education showed a significant correlation with anxiety scores (p = 0.027). Pain increased significantly during the procedure (p ± 1.4) and applicator removal (4.74 ± 1.5) turned out to be the most painful parts of the procedure. No correlation was found between pain and anxiety levels. Conclusion: Intracavitary multifraction high-dose rate brachytherapy is associated with mild to moderate levels of pain and anxiety, although a subset of patients reported more severe symptoms and may require additional medical and psychological support, with particular emphasis on bed-rest duration and applicator removal. The development of effective interventions (both pharmacological and non-pharmacological) is needed to improve women’s experiences of brachytherapy for locally advanced cervical cancer.

Clinical study of three dimensional conformal radiotherapy combined with intracavitary brachytherapy in the treatment of cervical cancer

Objective: The aim of our study was to evaluate the outcome and complications of cervical cancer patients undergoing conventional intracavitary brachytherapy (ICBT) treated with 3D-conformal radiotherapy (3DCRT). Methods: Sixty cervical cancer patients were divided randomly into the conformal group and the conventional group. Thirty patients treated with 3D-conformal radiotherapy in the 3DCRT group, when the whole pelvic received DT 40 Gy, a planning CT scan of each patient was obtained and the second 3DCRT therapy plan was taken. Then, continued to irradiate to 50 Gy. At last, 3DCRT was boosted at local involved volumes to the total dose of 60 Gy. When 3DCRT was combined with intracavitary brachytherapy, the dose of brachytherapy to point A was 30 Gy/5 fractions. In the conventional group, after a total tumor dose of 40 Gy was delivered by the whole pelvic irradiation, the four-field technique was used to irradiate the total pelvic and regional nodes (median dose of 10 Gy), and the involved volumes were boosted to 60 Gy and the dose of brachytherapy to point A was 30 Gy-36 Gy/5-6 fractions. Moreover, both groups were combined with intracavitary brachytherapy respectively. Results: The 1, 2, 3-year survival rates for the 3DCRT group and the conventional group were 96.7%, 93.3%, 90.0% and 86.6%, 76.7%, 70% respectively (P = 0.04, P = 0.02 and P = 0.02). There was a statistically significant difference between the two groups. Compared to the two groups each other in toxic effects, except for the I-II grade rectal and bladder reaction and pelvic fibrosis which was lower in the 3DCRT group (P = 0. 007, P = 0. 006 and P = 0. 015), the side effects were similar and well tolerated in two groups. Conclusion: The all-course 3DCRT combined with intracavitary brachytherapy can be considered as an effective and feasible approach to cervical cancer and may significantly improve the survival rate and reduce the late toxicity. This new role for 3DCRT merits need further evaluation with large patient numbers and longer follows up.

Clinical Report on Californium-252 Neutron Intraluminal Brachytherapy Combined with External Irradiation for Cervical Carcinoma Treatment

OBJECTIVE To observe the curative effects and complications of californium-252 （^252Cf） neutron intraluminal brachytherapy （IBT） combined with external irradiation （El） for treatment of cervical carcinoma.METHODS From December 2000 to December 2004, 128 cases of cer vical carcinoma staged into IIA-IIIB according to the International Federation of Gynecology and Obstetrics （FIGO） standards were treated with ^252Cf neutron IBT using 8-10 Gy per fraction, once a week. The total dose at reference A point was 36-40 Gy in 4-5 fractions. From the second day after ^252Cf neutron IBT treatment, the whole pelvic cavity was treated with ^60Co y-ray El, applying 2 Gy per fraction, 4 times per week. After 20-25Gy of El, the center of the whole pelvic field was blocked with 4 cm of lead in width. The total dose of El was 45-50 Gy.RESULTS The short-term therapeutic effects were CR 95.3% and PR 4.7%. The 3 and 5-year local control rates were 93.5% and 87.9%. The overall 3-year survival rate was 87.5% and for Stages Ⅱ and Ⅲ , 90.9% and 81.5% respectively; the overall 5-year survival rate was 70% and for Stages II and III, 76.2% and 61% respectively. The rate of radiation complications was 4.7% for radiation cystitis, 7.8% for radiation proctitis, 6.3% for vagina contracture and adhesion and 5.5% for protracted radiation proctitis.CONCLUSION An combination of ^252Cf neutron IBT with El for treatment of cervical carcinoma can be well-tolerated by cervical carcinoma patients. The rate of local tumor control is high and radiation complications are few.

Experiences of Women Receiving Multifraction High Dose-Rate Brachytherapy for Cervical Cancer: A Prospective Qualitative Study

Objective: The aim of this study was to establish cervical cancer patients’ expectations and experiences during high dose-rate (HDR) intracavitary brachytherapy procedure, as part of a process to develop guidelines for quality patient-centered care. Methodology: A prospective, qualitative study with a descriptive phenomenological approach was used. Purposive sampling was carried out to recruit 31 women undergoing HDR brachytherapy for cervical cancer from June to August 2020 at the National Institute of Oncology in Rabat. Semi-structured, one-to-one interviews guided by a theme list were conducted by a female radiation oncologist in Arabic before, during and after treatment. The following aspects were discussed: expectations, experiences in the waiting room, in the treatment room, and suggestions for improvement. Data was transcribed, translated and thematic analysis performed. Results: Most of the patients felt unprepared and did not have a clear understanding of brachytherapy. Brachytherapy was a difficult experience causing fear and anxiety throughout treatment. Most women dreaded the procedure, before receiving the first treatment and even after having had one. Pain was a major problem for the participants. Some women compared this pain to childbirth, a process they preferred to brachytherapy. Patients agreed that the preventative medication received was not efficient to relieve the pain. Despite these negative experiences, patients were left with a positive outlook. Dialogue with the healthcare professionals, support from their family and fellow patients, envisaged outcomes and desires to heal were used to cope, whilst faith and spirituality gave them strength to endure the procedure. Conclusion: Women undergoing uterovaginal brachytherapy for cervical cancer experience pain and emotional distress. Providing patients with adequate information, more sensitive support during the procedure and debriefing afterwards could lessen feelings of fear and anxiety. Our findings advocate for the revision of pain management protocols. Further studies should be carried out to define patient-centered recommendations and provide quality care to this group of women.

Informational Needs in Women Undergoing Multifraction High Dose-Rate Brachytherapy for Cervical Cancer: A Prospective Qualitative Study

Objective: To identify the informational needs of Moroccan women receiving intracavitary brachytherapy for locally advanced cervical cancer as part of a process to develop guidelines for quality patient-centered care. Methodology: A prospective, qualitative study with a phenomenological approach was carried out at the Brachytherapy unit of the National Institute of Oncology in Rabat, Morocco. Purposive sampling was used to recruit 31 patients undergoing high dose-rate brachytherapy for cervical cancer from July 2020 to August 2020. Semi-structured, one-to-one interviews were conducted by a female radiation oncologist in Arabic, guided by a theme list. The interviews were translated and a thematic analysis was performed. Results: Data saturation was achieved having interviewing 31 participants, aged 27 - 70 years. Findings on patients’ informational needs were the overarching theme and form the focus of this article. The informational needs included: providing patients with disease- and treatment-related information in their home language;adequate information concerning pre-treatment preparation, possible side-effects, and sexual intercourse;and providing patients with informative material adapted to their needs as standard procedure. Conclusion: This study has identified unmet women’s informational needs during brachytherapy for cervical cancer. Providing patients with sufficient and understandable information, adequate preparation before the procedure, more sensitive support during the procedure, and debriefing afterward could lessen feelings of fear and anxiety towards treatment delivery. Guidelines with a patient-centered approach could thus be developed to be used as a tool to assist members of multidisciplinary teams in providing quality care to this group of women.

Relationship between Cell Proliferation and Apoptosis in Cervical Carcinoma

Objective To study the relationship between cell proliferation and apoptosis in cervical carcinoma and its clinical significance. Methods The cell proliferation and apoptosis of cervical epithelial cells in archival formalin-fixed, paraffin-embedded tissue sections of normal cervix, cervical intraepithelial neoplasms (GIN) and cervical squamous carcinoma were tested by using immunohistochemistry assay and DNA nick end-labeling technigue. The proliferation index (PI) and apoptosis index (AI) were calculated and their correlation with clinical and pathological data was analyzed.Results PI was gradually increased, but the AI and AI/PI ratio decreased from normal cervical epithelium, GIN to cervical carcinoma. There was no significant relationship among cell proliferation, apoptosis, clinical stages and pathological grades. High AI was always associated with a poor prognosis of the patients.Conclusion Cell proliferation and apoptosis allow to distinguish among normal epithelium, GIN and cervical carcinoma and are useful for the assessment of the malignant potential of tumor tissues.

Prognostic evaluation of postoperative adjuvant therapy for operable cervical cancer:10 years'experience of National Cancer Center in China

Objective： The aim of this study was to investigate the prognostic factors and to evaluate the impact of adjuvant therapy on clinical outcome for early-stage cervical cancer. Methods： The clinical-pathological data of all 1,335 patients with the International Federation of Gynecology and Obstetrics （FIGO） Ib-[Ia cervical cancer treated with primary radical surgery at the Chinese National Cancer Center between May 2007 and Dec 2013 were retrospectively reviewed. The median follow-up was 70 months. Results： Of all the patients, 61.6% of the cases received adjuvant therapy, with 5-year disease-free survival （DFS） of 92.1% and 5-year overall survival （OS） of 95.0%. In multivariate analysis, differentiation of G3 （P〈0.05）, lymph node metastasis （LNM, P〈0.05） and lymphovascular space invasion （LVSI, P〈0.05） were independent predictors for OS, while LNM （P〈0.05）, deep stroma invasion （DSI, P〈0.05） and LVSI （P〈0.05） were independent factors for DFS. The samples were stratified by histologic type, and cervical squamous cell carcinoma （SCC） was found to share the same independent factors except for differentiation of OS. As to patients with cervical adenocarcinoma/adenosquamons carcinoma （AC/ASC）, differentiation was the independent predictor of OS （P〈0.05）; and LVSI of DFS （P〈0.05）. Of 236 patients with high-risk factors, there was no significant difference in survival between concurrent chemoradiotherapy （CCRT, n=195）, radiotherapy （RT, n=24）, and chemotherapy （CT, n=17）. Among the 190 patients with LNM who underwent CCRT, 124 cases showed improved DFS after sequential CT （P=0.118）, with a recurrence rate decrease of 14%, though the difference was not statistically significant. Patients with single intermediate-risk factors like DSI or LVSI were found to partially benefit from adjuvant therapy, but the difference was not statistically significant. Conclusions： LNM, LVSI, DSI and differentiation were found to be independent prognostic factors for operable cervical cancer. Aggressive postoperative adjuvant therapy based on single risk factors in Chinese National Cancer Center could benefit survival. CCRT＋CT outperformed CCRT in high-risk patients. For patients with single non-high-risk factor, the role of adjuvant therapy needs to be further discussed.

Human Papillomavirus 16 E6,E7 siRNAs Inhibit Proliferation and Induce Apoptosis of SiHa Cervical Cancer Cells

Objective： To evaluate the effects of HPV16 E6/E7 siRNAs on cervical cancer SiHa cells. Methods： The expressions of the E6, E7, p53 and Rb genes were assayed by RT-PCR and Western-bloting respectively. The proliferation and apoptosis of the cells were evaluated by MTT and flow cytometry. Results： HPV 16 E6 and E7 oncogenes were selectivly downregulated by HPV 16 E6 and E7 siRNAs, which sustained at least 96 h by single dose siRNA. Furthermore, reduction of E6 and E7 oncogenes expression upregulated the expressions of P53 and RB protein and induced apoptosis in SiHa cells. Conclusion： Introduction of HPV16 E6/E7 siRNA might be a potentially potent and specific approach to inhibit proliferation and induce apoptosis of SiHa cervical cancer cells.

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

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

Relationship between the Expression of Telomerase and Human Papillomavirus Infection in Invasive Uterine Cervical Carcinoma

Telomerase activity was examined in invasive cervical carcinoma to assess whether it is activated during cervical malignant transformation and to look for its possible association with human papillomavirus （HPV） infection. Histologically confirmed invasive cervical carcinomas and benign cervices were assayed for telomerase activity by using a modified telomere repeat amplification protocol （TRAP）. The same cases were subjected to polymerase chain reaction （PCR） detection of HPV by using consensus primers and type-specific （HPV types 16 and 18） primers. Telomerase activity was detected in 40 of 45 （88.9%） invasive cervical carcinomas and 2 （all chronic cervicitis） of 50 （4%） benign cervical lesions. HPV was detected in 36 （24 HPV-16 and 4 HPV-18 cases） of 45 （80%） invasive cervical carcinomas and 20 （11 HPV-16 and 1 HPV-18 cases） of 50 （40%） benign cervical changes. There was a significant correlation between the expression of telomerase with histological grade （φ=0.44, P〈0.005）, but no correlation was found between telomerase expression and HPV-18 （P〉0.05）. Although larger sample studies are needed, there seems to be a clear association between telomerase upregulation and HPV status, mainly HPV-16 infection.

LOSS OF HETEROZYGOSITY ON CHROMOSOME 17p13.3 IN OVARIAN CANCER AND CERVICAL CANCER

Objective: To identify the loss of heterozygosity (LOH) on chromosome 17p13 3 in ovarian cancer and cervical cancer Methods: The frequency of LOH on chromosome 17p13 3 in DNA samples from 24 ovarian cancers, 9 cervical cancers, and 13 non malignant gynecological diseases were determined respectively, using Southern blot method with probe PYNZ 22 Results: LOH on 17p13 3 was found in 12 of 24 (50 0%) ovarian cancers (including a borderline mucinous cystadenoma), 4 of 9 (44 4%) cervical carcinomas, and 1 of 13 (7 7%) non malignant gynecological diseases, which was cervical intraepithelial neoplasm III (CIN III) ( P< 0 01) Conclusion: These results show that LOH on 17p13 3 is associated with ovarian cancer and cervical cancer, suggesting that detection of LOH on 17p13 3 may be helpful to understand the molecular pathogenesis of ovarian cancer and cervical cancer

Aberrant DNA methylation in cervical carcinogenesis

Persistent infection wit h high-risk types of human papillomavirus(HPV) is known to cause cervical cancer;however,additional genetic and epigenetic alterations are required for progression from precancerous disease to invasive cancer.DNA methylation is an early and frequent molecular alteration in cervical carcinogenesis.In this review,we summarize DNA methylation within the HPV genome and human genome and identify its clinical implications.Methylation of the HPV long control region(LCR) and L1 gene is common during cervical carcinogenesis and increases with the severity of the cervical neoplasm.The L1 gene of HPV16 and HPV18 is consistently hypermethylated in invasive cervical cancers and can potentially be used as a clinical marker of cancer progression.Moreover,promoters of tumor suppressor genes(TSGs) involved in many cellular pathways are methylated in cervical precursors and invasive cancers.Some are associated with squamous cell carcinomas,and others are associated with adenocarcinomas.Identification of methylated TSGs in Pap smear could be an adjuvant test in cervical cancer screening for triage of women with high-risk HPV,atypical squamous cells of undetermined significance,or low grade squamous intraepithelial lesion(LSIL).However,consistent panels must be validated for this approach to be translated to the clinic.Furthermore,reversion of methylated TSGs using demethylating drugs may be an alternative anticancer treatment,but demethylating drugs without toxic carcinogenic and mutagenic properties must be identified and validated.

<i>FAS</i>-670 Gene Promoter Region Polymorphism in Cervical Intraepithelial Neoplasia Grade 3 (CIN 3) and Invasive Cervical Cancer

The human papillomavirus (HPV) is the etiologic agent of genital cancer, but alone it is incapable of inducing oncogenesis. Rather, progression to invasive lesions is associated with host immunity and interference in the process of cellular apoptosis. Among the several genes involved in cell death, theFAS gene appears to be an important factor. The aim of this study was to evaluate whether there is an association between polymorphisms of the FAS-670 gene promoter region and preinvasive and invasive lesions of the cervix. The FAS gene was evaluated for the presence of polymorphisms using polymerase chain reaction and restriction fragment length polymorphism techniques in 225 blood samples for the control group, as well as cervical tissue from patients with cervical intraepithelial neoplasia grade 3 (CIN 3;75 cases) or invasive carcinoma (214 cases). The AG genotype of the FAS-670 gene promoter region was significantly more frequent in women with CIN 3, with an estimated risk of three times (OR = 3.0). No difference, however, was observed in the control group and women with cervical cancer. In women with cancer, the genotypes were similar in the different histological types and degree of tumor differentiation. Assessing allelic distribution (A or G), we observed no difference in frequency of genotypes in studied groups. These data suggest that polymorphism of the promoter region of the FAS-670 gene is associated with increased risk of CIN 3, but not for invasive cancer of the cervix.