Treatment Strategy For Cervical Cancer Research Articles

Shp2 expression is upregulated in cervical cancer, and Shp2 contributes to cell growth and migration and reduces sensitivity to cisplatin in cervical cancer cells

Src homology phosphotyrosine phosphatase 2 (Shp2) has been found to be overexpressed in cervical cancer tissues. However, the influence of Shp2 on the biological behavior and sensitivity to cisplatin of cervical cancer cells remains unclear. We aimed to assess Shp2 expression in cervical tissues and cell lines and to detect the influence of Shp2 knockdown and overexpression on the biological behavior and sensitivity to cisplatin in cervical cancer cells. We found that Shp2 expression was significantly upregulated in cervical cancer tissues and cell lines, and Shp2 overexpression was associated with lymph node metastasis and a high human papillomavirus (HPV) DNA load. Shp2 knockdown inhibited cell growth and migration and enhanced sensitivity to cisplatin in the HeLa and SiHa cervical cancer cell lines. In contrast, Shp2 overexpression had the opposite effects. These tumor-promoting effects of Shp2 may be partly related to Akt signaling. In conclusion, Shp2 is involved in the occurrence and development of cervical cancer and may confer cisplatin resistance in cervical cancer. Shp2 blockade may be a new strategy for cervical cancer treatment.

MRI of cervical cancer with a surgical perspective: staging, prognostic implications and pitfalls.

Magnetic resonance imaging (MRI) of the pelvis is the most reliable imaging modality for staging, treatment planning, and follow-up of cervical cancer; and its findings may now be incorporated into the International Federation of Gynecology and Obstetrics Federation (FIGO) 2018 clinical staging of cervical cancer. It is imperative that radiologists are familiar with the imaging appearance of the different stages of cervical cancer as well as the post-treatment changes and imaging pitfalls given the respective clinical manifestations, treatment regimens, and prognosis of an accurate diagnosis. In addition to the different stages of cervical cancer, we address the imaging techniques for diagnosis, staging and treatment implications as well as the changes of the new FIGO staging system. The use of MRI to diagnose and stage cervical cancer is steadily increasing and the new FIGO stagi ng system, previously based on clinical examination, now allows the staging or change of staging based on the imaging findings. MRI can evaluate the extent of disease because of its excellent contrast resolution for pelvic tissues and organs, high accuracy and detailed elaboration of the cervical/uterovaginal anatomy. Relevant anatomy, including normal MRI appearance of the cervix, parametria and pelvic ligaments; different stages of cervical cancer on MRI with prognostic and therapeutic implications; MRI sequences, other imaging modalities used in the staging and follow-up, treatment of different stages and the appearance of the cervix and cervical cancer post-treatment. Since clinical implications and therapeutic strategies for cervical cancer treatment vary tremendously according to degree of tumor extension, familiarity with relevant MRI techniques and findings is essential for radiologists. It is important that radiologists interpreting pelvic MRI are aware with the different stages of cervical cancer to provide useful information regarding treatment and prognosis. Pitfalls regarding the interpretation of tumor extension can interfere with an accurate diagnosis and have significant therapeutic implications.

Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.

The Japan Society of Gynecologic Oncology (JSGO) Guidelines 2017 for the Treatment of Uterine Cervical Cancer are for the purpose of providing standard treatment strategies for cervical cancer, indicating treatment methods currently considered appropriate for cervical cancer, minimizing variances in treatment methods among institutions, improving the safety of treatment and prognosis of diseases, reducing the economic and psychosomatic burden of patients by promoting performance of appropriate treatment, and enhancing mutual understanding between patients and healthcare professionals. The guidelines were prepared through consensus of the JSGO Guideline Committee, based on careful review of evidence gathered through the literature searches and in view of the medical health insurance system and actual clinical practice situations in Japan. The guidelines comprise eight chapters and five algorithms. The main features of the 2017 revision are as follows: (1) evidence was collected using a search formula and with cooperation of the Japan Library Association. The bibliographical search formula was placed at the end of the book; (2) regarding clinical questions (CQs) where evidence or clinical inspection in Japan was lacking, opinions of the Guidelines Committee were described as "proposals for future directions"; (3) cervical intraepithelial neoplasia (CIN) 3 and adenocarcinoma in situ (AIS) were treated as a cervical precancerous lesion; (4) the CQs of endoscopic surgery, radical trachelectomy, and sentinel node biopsy were newly added in Chapter3, "primary treatment for stage IB-II cervical cancer"; and (5) the CQ about hormone replacement therapy after cancer treatment was newly established. Each recommendation is accompanied by a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSGO Guidelines 2017 for the Treatment of Uterine Cervical Cancer.

Long non-coding RNA TTN-AS1 promotes cell growth and metastasis in cervical cancer via miR-573/E2F3

Long non-coding RNAs (lncRNAs) are a crucial member of non-coding RNA family, and increasing evidence demonstrates that lncRNAs participate in the initiation and progression of cancers. Our study aimed to explore the role of lncRNA TTN-AS1 in cervical cancer (CC) development. In the present study, our results showed that TTN-AS1 was substantially increased in CC tissues and cell lines, high expression of TTN-AS1 was correlated with advanced FIGO stage, poor differentiation, lymph node metastasis, and poor overall survival of CC patients. Function assays showed that TTN-AS1 inhibition decreased the proliferation and invasion of CC cells both in vitro and in vivo. Mechanistically, we revealed that TTN-AS1 could positively modulate E2F3 expression via sponging miR-573 in CC cells. Together, our study revealed that lncRNA TTN-AS1 was involved in the progression of CC cells by regulation of miR-573-E2F3 axis, which offered a new insight into the treatment strategies of CC.

Simultaneous multiparametric PET/MRI for the assessment of therapeutic response to chemotherapy or concurrent chemoradiotherapy of cervical cancer patients: Preliminary results

PurposeTo assess the response to initial treatment strategies of cervical cancer using multiparametric-PET/MRI. Material and methodsPET/MR-derived morphological (tumor size), functional (DWI, DCE-MRI) and metabolic (18F-FDG PET) parameters were acquired in pre- and posttreatment examinations of 8 patients. Besides RECIST- and PERCIST-criteria, functional quantitative parameters were used to assess therapeutic response. ResultsRECIST- and PERCIST-response criteria demonstrated high correlations for the differentiation between therapy-responders and non-responders, which was additionally reflected by functional (DWI, DCE-MRI) quantitative imaging parameters. ConclusionMultiparametric-PET/MRI bears the potential of a more comprehensive response assessment of initial treatment strategies in cervical cancer patients.

Therapeutic significance of targeting survivin in cervical cancer and possibility of combination therapy with TRAIL.

Loss of p53 function due to human papillomavirus (HPV) infection induces resistance to apoptosis in cervical cancer cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in a p53-independent manner, may provide an alternative strategy for treating cervical cancer. Survivin, an antiapoptotic protein that is highly expressed in cancer cells, regulates apoptosis and the cell cycle. Here, we investigated the therapeutic potential of targeting survivin, while focusing on the TRAIL-induced apoptosis pathway. The viability and cell cycle of HPV16-positive CaSki and SiHa cells were assessed after survivin knockdown by small interfering RNA (si-survivin). E-cadherin expression was also assessed after si-survivin treatment, using western blotting. SiHa (a TRAIL-resistant cell line) was used for further studies. The small molecule YM155 and resveratrol (RVT; a polyphenol with the potential to suppress survivin expression) were used as survivin inhibitors. The effects of si-survivin and survivin inhibitors on TRAIL- or cisplatin (CDDP)-induced apoptosis were analyzed by annexin-V staining. si-survivin treatment decreased cell viability and led to G2/M arrest, accompanied by morphological changes and E-cadherin upregulation in both CaSki and SiHa cells. si-survivin and YM155 synergistically sensitized TRAIL-resistant SiHa cells to TRAIL-induced apoptosis (p < 0.05). However, si-survivin and YM155 only slightly increased CDDP-induced apoptosis. RVT markedly enhanced TRAIL-induced apoptosis by suppressing survivin expression. Targeting of survivin expression might be an ideal strategy for cervical cancer treatment as it would decrease viable cell number and enhance apoptosis sensitivity. Further, combination therapy with TRAIL, rather than CDDP, may be compatible with the proposed survivin-targeting strategy.

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

ABSTRACTVX680 is a potent and selective inhibitor that targets the Aurora kinase family. The p38 mitogen-activated protein kinase (MAPK) regulates a large number of cellular pathways and plays an important role in the regulation of cell survival and apoptosis. This study aimed to evaluate the effect of VX680 on cervical cancer cells and investigate whether the effects on apoptosis are enhanced by the ablation of p38 MAPK activation. The results suggested that VX680 inhibited the proliferation of cervical cancer cells by causing G2/M phase arrest and endoreduplication and that the apoptotic effect was attenuated by the activation of p38 MAPK. However, the addition of BIRB796, which is an important p38 MAPK inhibitor, effectively eliminated the expression of p-p38 and hence significantly enhanced the cell death induced by VX680 in vitro. Further study demonstrated that BIRB796 cooperated with VX680 to suppress cervical cancer cell growth in a mouse xenograft model. Taken together, our results demonstrated that VX680 induced cell cycle arrest and endoreduplication in human cervical cancer cells. Combined treatment with VX680 and BIRB796 synergistically inhibited tumor growth both in vitro and in vivo. Dual blockade of Aurora kinases and p38 MAPK is therefore a promising strategy for cervical cancer treatment.

Characterization of long non-coding RNA expression profiles in lymph node metastasis of early-stage cervical cancer.

Pelvic lymph node metastasis (PLNM) is an independent prognostic parameter and determines the treatment strategies of cervical cancer. Increasing evidence indicates that long non-coding RNAs (lncRNAs) play a crucial role in the process of tumor biological functions. This study aimed to mine lymph node metastasis-associated lncRNAs and investigate their potential pathophysiological mechanism in cervical cancer lymph node metastasis. We applied the lncRNA-mining approach to identify lncRNA transcripts represented on Affymetrix human genome U133 plus 2.0 microarrays from Gene Expression Omnibus (GEO) and then by validation in clinical specimens. The biological role and molecular mechanism of these lncRNAs were predicted by bioinformatic analysis. Subsequently, a receiver operating characteristic (ROC) curve and survival curve were conducted to evaluate the diagnostic and prognostic value of candidate lncRNAs. In total, 234 differentially expressed lncRNAs were identified to significantly associate with pelvic lymph node metastasis in early-stage cervical cancer. Our qRT-PCR results were consistent with the mining analysis (P<0.05). The functional enrichment analysis suggested that these lncRNAs may be involved in the biological process of lymph node metastasis. The ROC curves demonstrated satisfactory discrimination power of MIR100HG and AC024560.2 with areas under the curve of 0.801 and 0.837, respectively. Survival curve also indicated that patients with high MIR100HG expression had a tendency of poor prognosis. This is the first study to successfully mine the lncRNA expression patterns in PLNM of early-stage cervical cancer. MIR100HG and AC024560.2 may be a potential biomarkers of PLNM and these lncRNAs may provide broader perspective for combating cervical cancer metastasis.

Hyperthermia Selectively Targets Human Papillomavirus in Cervical Tumors via p53-Dependent Apoptosis.

Human papillomavirus (HPV) is associated with cervical cancer, the third most common cancer in women. The high-risk HPV types 16 and 18 are found in over 70% of cervical cancers and produce the oncoprotein, early protein 6 (E6), which binds to p53 and mediates its ubiquitination and degradation. Targeting E6 has been shown to be a promising treatment option to eliminate HPV-positive tumor cells. In addition, combined hyperthermia with radiation is a very effective treatment strategy for cervical cancer. In this study, we examined the effect of hyperthermia on HPV-positive cells using cervical cancer cell lines infected with HPV 16 and 18, in vivo tumor models, and ex vivo-treated patient biopsies. Strikingly, we demonstrate that a clinically relevant hyperthermia temperature of 42 °C for 1 hour resulted in E6 degradation, thereby preventing the formation of the E6-p53 complex and enabling p53-dependent apoptosis and G2-phase arrest. Moreover, hyperthermia combined with p53 depletion restored both the cell-cycle distribution and apoptosis to control levels. Collectively, our findings provide new insights into the treatment of HPV-positive cervical cancer and suggest that hyperthermia therapy could improve patient outcomes.

ID: 80: Intravaginal Fc-fused IL-7 attract DNA vaccine-induced CD8 T cell in the genital tract

Cervical cancer is one of the leading causes of cancer death in woman worldwide, and about 75% of its case are caused by persistent infection with the most common high-risk human papilloma virus (HPV) types. Recent studies indicate the importance of systemic immune activation and higher number of T-cell trafficking at the tumor site correlates with positive results. Systemic IL-7 has been reported to have the ability to enhance the magnitude and intensity of the antigen-specific T cell response. However, It is not well known the role of IL-7 in mucosal tissue. In this study, we reveal that intravaginal IL-7-Fc administration induces upregulation of T cell recruitment-related chemokine in the genital tract. These chemokine attract CD8+ T cells expressing their receptor. Intravaginal instillation of IL-7-Fc after intramuscular DNA vaccination increase the number of vaccination-induced CD8 T cell in the genital mucosa of mice, with enhance the systemic DNA-induced CD8+ T cell response in the spleen. Most interestingly, intravaginal IL-7-Fc following DNA vaccination increase survival rate than DNA alone group in orthotopic murine cervical cancer model. These findings suggest that combination treatment of mucosal IL-7-Fc administration followed systemic therapeutic vaccination is an effective strategy for cervical cancer treatment.

Suivi après radiothérapie pour un cancer du col utérin

Radiation therapy plays a central role in treatment strategies of cervical cancer. Follow-up after external pelvic radiation therapy and brachytherapy is based upon French and international specific recommendations. It aims to assess early tumour response, and to detect local or metastatic recurrences which can be suitable for salvage treatment. Follow-up after radiation therapy for cervical cancer should also assess gastro-intestinal, urinary and sexual toxicities which may have an impact on quality of life. This is a major concern in the evaluation of the results of intensity-modulated radiation therapy (IMRT) and MRI-guided brachytherapy, which should lead to a better local control and to a better bowel tolerance.

Aldehyde Dehydrogenase 1 Expression Predicts Chemoresistance and Poor Clinical Outcomes in Patients with Locally Advanced Cervical Cancer Treated with Neoadjuvant Chemotherapy Prior to Radical Hysterectomy

Neoadjuvant chemotherapy (NAC) is an important treatment strategy for cervical cancer; however, few predictive markers of the response to NAC exist. Aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, is associated with chemoresistance in a variety of cancers. This study attempted to investigate the value of ALDH1 as a predictive marker of chemosensitivity and its prognostic value in cervical cancer patients treated with NAC. Immunohistochemistry was used to evaluate ALDH1 expression in matched pre- and post-NAC tumor samples from 52 patients with cervical cancer. Kaplan-Meier analysis and a Cox proportional hazards regression model were applied to determine overall survival (OS) and disease-free survival (DFS). Fourteen patients (26.9 %) had ALDH1-positive tumors pre-NAC, and ALDH1 expression pre-NAC was significantly associated with a low clinical chemotherapy response rate and clinical non-response. Twenty-two patients (42.3 %) had ALDH1-positive tumors post-NAC, and ALDH1 expression post-NAC was associated with poor DFS and OS (both p = 0.004). Multivariate analysis revealed that ALDH1 expression post-NAC was an independent prognostic factor for OS (hazard ratio 3.513; p = 0.033). Moreover, we observed that ALDH1 expression was increased after NAC in 18 patients (36.7 %). Increased levels of ALDH1 expression after NAC predicted poor DFS and OS (p = 0.013 and p = 0.08, respectively). Our findings suggest that ALDH1 expression pre-NAC may be a predictive marker for response to NAC, and ALDH1 expression post-NAC could be a prognostic marker for cervical cancer.

Japan Society of Gynecologic Oncology guidelines 2011 for the treatment of uterine cervical cancer.

The second edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of uterine cervical cancer was published in 2011. The guidelines comprise eight chapters and five algorithms. They were prepared by consensus among the members of the Japan Society of Gynecologic Oncology Guidelines Formulation Committee and Evaluation Committee and are based on a careful review of the evidence obtained from the literature, health insurance system, and actual clinical settings in Japan. The highlights of the 2011 revision are (1) the recommended grades have been changed to five stages--A, B, C1, C2, and D; (2) the revisions are consistent with the new International Federation of Gynecology and Obstetrics staging system; (3) the roles are shared between the 'Japanese classification of cervical cancer' and the new guidelines; (4) clinical questions related to adenocarcinoma have been revised; and (5) a clinical question regarding cervical cancer in pregnant patients has been added. Each chapter includes a clinical question, recommendations, background, objectives, explanations, and references. Each recommendation is accompanied by a classification of recommendation categories. The objective of these guidelines is to update the standard treatment strategies for cervical cancer, thus eliminating unnecessary and insufficient treatment.

The Role of PET/CT in the Management of Cervical Cancer

OBJECTIVE. Cervical cancer is the second most common malignancy in women worldwide and the third most common cause of cancer mortality in the United States. The aim of this article is to describe cervical cancer and outline the value of (18)F-FDG PET/CT in the management of cervical malignancy. CONCLUSION. The value of PET/CT has been found in staging and treatment strategy for cervical cancer. FDG PET/CT facilitates decision-making and radiation treatment planning and provides important information about treatment response, disease recurrence, and long-term survival.

Larynx‐Preserving Limited Resection and Free Jejunal Graft For Carcinoma of the Cervical Esophagus

There is no generally accepted treatment strategy for cervical cancer. The aim of this study was to evaluate the safety and efficacy of larynx-preserving limited resection with free jejunal graft for cervical esophageal cancer. We retrospectively reviewed data of 58 patients with cervical esophageal cancer who underwent limited resection and free jejunal graft with or without laryngeal preservation. Among them, 45 patients received neoadjuvant treatment. Larynx-preserving surgery was conducted in 33 of the 58 patients (56.9%). A higher proportion of patients who underwent laryngopharyngectomy with cervical esophagectomy (larynx-nonpreserving group) had cT4 tumors than those who underwent larynx-preserving cervical esophagectomy (larynx-preserving group) (72 vs. 12%). The overall incidence of postoperative complications was similar in the two groups (56 vs. 52%). The 5-year survival rate was 44.9% for the entire group. Laryngeal preservation did not reduce overall survival compared with the larynx-nonpreserving operation (5-year survival rate: 57.8 vs. 25.8%). Multivariate analysis identified the number of metastatic lymph nodes as the only independent prognostic factor. The present study demonstrated that larynx-preserving limited resection with free jejunal graft is feasible. Also, this approach did not worsen the prognosis compared with the larynx-nonpreserving operation. Limited resection with free jejunal graft and laryngeal preservation is a promising treatment strategy for cervical esophageal cancer.

Targeting PDGF Signaling in Carcinoma-Associated Fibroblasts Controls Cervical Cancer in Mouse Model

Cervical cancer is one of the most prevalent malignancies in women worldwide and is the leading cause of cancer death for women in developing countries [1]. While early detection via the Pap test as well as treatment by surgery and chemoradiotherapy has reduced mortality from this disease, the prognosis is poor if the disease is detected at an advanced stage [2]. Thus new treatment strategies for cervical cancer are needed. In this issue of PLoS Medicine, Kristian Pietras and colleagues, using a mouse model of cervical carcinogenesis, provide compelling evidence that targeting platelet-derived growth factor (PDGF) signaling, primarily in carcinoma-associated fibroblasts (CAFs), can slow the progression of this disease and even impair the growth of invasive carcinomas [3]. By offering preliminary evidence for the presence of PDGF receptors in a limited number of human cervical cancer biopsies, these authors also suggest that the drugs approved by the United States Food and Drug Administration (FDA) that target PDGF signaling, such as imatinib mesylate (Gleevec in the US; Glivec in Europe and Australia, Novartis), be tested in the clinic for this malignancy.