Treatment Modality For Cervical Cancer Research Articles

ZIP14 Affects the Proliferation, Apoptosis, and Migration of Cervical Cancer Cells by Regulating the P38 MAPK Pathway.

Cervical cancer (CC) remains a major public health concern and is a leading cause of female mortality worldwide. Understanding the molecular basis of its pathogenesis is essential for the development of novel therapeutic strategies. In this study, we aimed to dissect the role of a specific molecule, ZIP14, in the initiation and progression of CC. We used Gene Expression Omnibus for target gene identification, while KEGG was used to delineate CC-related pathways. Proliferation, migration, and apoptosis levels in CC cells were assessed using CCK8, Transwell, and flow cytometry, respectively. The effect of the target genes on the in vivo tumorigenesis of CC cells was evaluated using the subcutaneous tumorigenesis assay. ZIP14 (SLC39A14) was found to be underexpressed in CC samples. Our KEGG pathway analysis revealed the potential involvement of the P38 mitogen-activated protein kinase (MAPK) pathway in CC pathogenesis. Overexpression of ZIP14 in HeLa and Caski cells increased p38 phosphorylation, inhibited cell growth and migration, and enhanced apoptosis. Conversely, ZIP14 knockdown produced the opposite effects. Importantly, the bioeffects induced by ZIP14 overexpression could be counteracted by the p38 MAPK pathway inhibitor SB203580. In vivo experiments further confirmed the influence of ZIP14 on CC cell migration. Our study is the first to elucidate the pivotal role of ZIP14 in the pathogenesis of CC, revealing its inhibitory effects through the activation of the p38 MAPK signaling pathway. The discovery not only provides a deeper understanding of CC's molecular underpinnings, but also highlights ZIP14 as a promising therapeutic target. As ZIP14 holds significant potential for therapeutic interventions, our findings lay a robust foundation for further studies and pave the way for the exploration of novel treatment modalities for cervical cancer.

Optimizing Online Adaptation Timing in the Treatment of Locally Advanced Cervical Cancer

Purpose/Objective: Online adaptive radiotherapy (ART) has emerged as a new treatment modality for cervical cancer. Daily online adapting improves target coverage and OAR sparing compared to traditional image-guided radiation therapy (IGRT); however, the required resources may not be feasible in a busy clinical setting. Less frequent adapting may still benefit cervical cancer patients due to large volume changes of the uterocervix of the treatment course. In this study, the dosimetry from different online adapt-on-demand schedules is compared.Materials/Methods: A retrospective cohort of 10 patients with cervical cancer treated with 260 fractions of definitive daily online adaptive radiotherapy was included. Plans with different adaptation schedules were simulated with adaptations weekly, every other week, once during treatment, and no adaptations (IGRT). These plans were applied to the synthetic CTs and contours generated during the patient's delivered daily adaptive workflow. The dosimetry of the weekly replan, every other week replan, once replan, and IGRT plans were compared using a paired t-test.Results: When compared to traditional IGRT plans, weekly and every other week ART plans had similar CTV coverage, but statistically significant improved sparing of OARs. Weekly and every other week ART had reduced bowel bag V40 by 1.57% and 1.41%, bladder V40 by 3.82% and 1.64%, rectum V40 by 8.49% and 7.50%, and bone marrow Dmean by 0.81% and 0.61%, respectively. Plans with a single adaptation had statistically significantly worse target coverage, and moderate improvements in OAR sparing. Of the 18 dose metrics evaluated, improvements were seen in 15 for weekly ART, 14 for every other week ART, and 10 for single ART plans when compared to IGRT. When every other week ART was compared to weekly ART, both plans had similar CTV coverage and OAR sparing with only small improvements in bone marrow dosimetry with weekly ART.Conclusions: This retrospective work compares different adapt on demand treatment schedules using data collected from patients treated with daily online adaptive radiotherapy. Results suggest weekly or every other week online ART is beneficial for reduced OAR dose compared to IGRT by exploiting the gradual changes in the uterocervix target volume.

Dosimetric Difference of Urinary Bladder and Rectum in Patients Undergoing Intracavitary Brachytherapy for Cervical Cancer under Procedural Sedation and General Anesthesia: A Survey at Bugando Cancer Center and Ocean Road Cancer Institute

Background: High-Dose-Rate Intracavitary Brachytherapy (HDR-ICBT) is a commonly employed treatment modality for cervical cancer, delivering a high dose of radiation directly to the tumor site while minimizing exposure to surrounding healthy tissues. Anaesthesia administration during HDR-ICBT varies, with some centres using Sedation (CS) and others employing General Anaesthesia (GA). Despite the widespread use of these anaesthesia techniques, their potential impact on dosimetric outcomes, particularly in the urinary bladder and rectum, remains an area of interest and investigation. Objective: This study aimed to determine the dosimetric difference in the urinary bladder and rectum doses among cervical cancer patients undergoing HDR-ICBT under CS and GA. The study was conducted at Bugando Cancer Centre (BCC) and Ocean Road Cancer Institute (ORCI) to compare the dosimetric outcomes between the two anaesthesia techniques. Methods: A total of 273 patients who underwent HDR-ICBT for cervical cancer were included in the study. Patients were divided into two groups based on the anaesthesia technique used during the procedure: 143 patients received GA, and 130 patients received CS. Dosimetric parameters of the urinary bladder and rectum doses were collected and analysed using descriptive statistics and the independent samples t-test. Results: The findings demonstrated a statistically significant dosimetric difference in the mean urinary bladder dose between patients treated under GA and CS (p < 0.001). Patients under GA received a significantly lower mean urinary bladder dose compared to those under CS. However, no statistically significant difference was observed in the mean rectum dose between the two anaesthesia groups (p = 0.689). Conclusion: The study reveals that the choice of anesthesia technique significantly impacts the urinary bladder dose during HDR-ICBT for cervical cancer. Patients receiving GA had a lower mean urinary bladder dose compared to those under CS. However, no significant dosimetric difference was observed in the mean rectum dose between the two anesthesia groups. These findings emphasize the importance of considering anesthesia techniques during treatment planning to optimize dosimetric outcomes and patient safety in HDR-ICBT. Further investigation and long-term follow-up are warranted to validate and expand upon these results. Collaboration between radiation oncologists and anesthesia teams is crucial to enhance treatment efficacy and minimize potential complications during HDR-ICBT for cervical cancer

Review of the Standard and Advanced Screening, Staging Systems and Treatment Modalities for Cervical Cancer.

Simple SummaryThis review discusses the timeline and development of the recommended screening tests, diagnosis system, and therapeutics implemented in clinics for precancer and cancer of the uterine cervix. The incorporation of the latest automation, machine learning modules, and state-of-the-art technologies into these aspects are also discussed.Cancer arising from the uterine cervix is the fourth most common cause of cancer death among women worldwide. Almost 90% of cervical cancer mortality has occurred in low- and middle-income countries. One of the major aetiologies contributing to cervical cancer is the persistent infection by the cancer-causing types of the human papillomavirus. The disease is preventable if the premalignant lesion is detected early and managed effectively. In this review, we outlined the standard guidelines that have been introduced and implemented worldwide for decades, including the cytology, the HPV detection and genotyping, and the immunostaining of surrogate markers. In addition, the staging system used to classify the premalignancy and malignancy of the uterine cervix, as well as the safety and efficacy of the various treatment modalities in clinical trials for cervical cancers, are also discussed. In this millennial world, the advancements in computer-aided technology, including robotic modules and artificial intelligence (AI), are also incorporated into the screening, diagnostic, and treatment platforms. These innovations reduce the dependence on specialists and technologists, as well as the work burden and time incurred for sample processing. However, concerns over the practicality of these advancements remain, due to the high cost, lack of flexibility, and the judgment of a trained professional that is currently not replaceable by a machine.

Radiotherapy-induced uterine cacinosarcoma: A case report and review of the literature.

Radiation therapy is a very effective treatment modality for cervical cancer, but unfortunately, ionizing radiation is associated with many side effects, including secondary cancer formation. We report a case of carcinosarcoma of the uterus in a woman with a history of pelvic irradiation for cervical carcinoma. A review of the literature was performed to present the incidence, optimal management, and prognosis for post-radiation uterine carcinosarcoma.

Three-dimensional deep neural network for automatic delineation of cervical cancer in planning computed tomography images.

PurposeRadiation therapy is an essential treatment modality for cervical cancer, while accurate and efficient segmentation methods are needed to improve the workflow. In this study, a three‐dimensional V‐net model is proposed to automatically segment clinical target volume (CTV) and organs at risk (OARs), and to provide prospective guidance for low lose area.Material and methodsA total of 130 CT datasets were included. Ninety cases were randomly selected as the training data, with 10 cases used as the validation data, and the remaining 30 cases as testing data. The V‐net model was implemented with Tensorflow package to segment the CTV and OARs, as well as regions of 5 Gy, 10 Gy, 15 Gy, and 20 Gy isodose lines covered. The auto‐segmentation by V‐net was compared to auto‐segmentation by U‐net. Four representative parameters were calculated to evaluate the accuracy of the delineation, including Dice similarity coefficients (DSC), Jaccard index (JI), average surface distance (ASD), and Hausdorff distance (HD).ResultsThe V‐net and U‐net achieved the average DSC value for CTV of 0.85 and 0.83, average JI values of 0.77 and 0.75, average ASD values of 2.58 and 2.26, average HD of 11.2 and 10.08, respectively. As for the OARs, the performance of the V‐net model in the colon was significantly better than the U‐net model (p = 0.046), and the performance in the kidney, bladder, femoral head, and pelvic bones were comparable to the U‐net model. For prediction of low‐dose areas, the average DSC of the patients’ 5 Gy dose area in the test set were 0.88 and 0.83, for V‐net and U‐net, respectively.ConclusionsIt is feasible to use the V‐Net model to automatically segment cervical cancer CTV and OARs to achieve a more efficient radiotherapy workflow. In the delineation of most target areas and OARs, the performance of V‐net is better than U‐net. It also offers advantages with its feature of predicting the low‐dose area prospectively before radiation therapy (RT).

Development of a management guide wheel for cervical cancer

We designed and developed a management guide wheel for cervical cancer to facilitate a standard approach and improve the quality of care in managing patients diagnosed with different stages of cervical cancer. Each step of the wheel considers the patient’s current medical condition, FIGO stage, and the possible treatment modalities for cervical cancer in her case. We reviewed existing international guidelines on the management of cervical cancer and compared their respective recommendations. This guide wheel is based on recommendations by the following organizations: the National Comprehensive Cancer Network (NCCN), the Society of Gynecologic Oncology (SGO), the European Society of Gynaecological Oncology (ESGO), the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), the British Gynaecological Cancer Society (BGCS) and the International Federation of Gynecology and Obstetrics (FIGO).

Enhancement of Conventional and Photodynamic Therapy for Treatment of Cervical Cancer with Cannabidiol.

Cervical cancer (CC) is the fourth most diagnosed cancer in women worldwide. Conventional treatments include surgery, chemo- and radiotherapy, however these are invasive and may cause severe side effects. Furthermore, approximately 70% of late-stage CC patients experience metastasis, due to treatment resistance and limitations. Thus, there is a dire need to investigate alternative therapeutic combination therapies. Photodynamic therapy (PDT) is an alternative CC treatment modality that has been clinically proven to treat primary CC, as well as to limit secondary metastasis. Since PDT is a non-invasive localized treatment, with fewer side effects and lessened resistance to dose repeats, it is considered far more advantageous. However, more clinical trials are required to refine its delivery and dosing, as well as improve its ability to activate specific immune responses to eradicate secondary CC spread. Cannabidiol (CBD) isolates have been shown to exert in vitro CC anticancer effects, causing apoptosis post treatment, as well as inducing specific immune responses, which obstruct tumor invasion and angiogenesis, and so hinder CC metastatic spread. This review paper discusses the current conventional and alternative PDT treatment modalities for CC, as well as their limitations over the last 10 years. It has a particular focus on the combinative administration of CBD with these treatments in order to prevent CC secondary migration and so possibly encourage future research studies to focus on this synergistic effect to eradicate CC.

A systematic review of the impact of contemporary treatment modalities for cervical cancer on women's self-reported health-related quality of life.

Given the high survival rate of cervical cancer patients, understanding women's health-related quality of life (HRQL) during and after treatment is of major clinical importance. We conducted a systematic review to synthesize all available evidence about the effects of each contemporary treatment modality for cervical cancer on all dimensions of women's HRQL, including symptoms, functioning, and global HRQL. We searched four electronic databases from January 2000 to September 2019, cross-referenced and searched by author name for studies of patients treated for cervical cancer that reported patient-reported outcomes (PROs) before treatment and with at least one post-treatment measurement. Two independent reviewers applied inclusion and quality criteria and extracted findings. Studies were categorized by treatment to determine specific treatment effects on PROs. Results were narratively summarized. We found twenty-nine papers reporting 23 studies. After treatments with curative intent for early or locally advanced disease, lymphedema, diarrhea, menopausal symptoms, tight and shorter vagina, pain during intercourse, and sexual worries remained long-term problems; however, sexual activity improved over time. HRQL and psychological distress were impacted during treatment with also worsening of global HRQL but improved 3-6months after treatment. In patients with metastatic or recurrent disease, pain improved during palliative treatment or remained stable, with no differences in global HRQL found over time. Whereas most symptoms worsen during treatment and improve in the first 3months after completing treatment, symptoms like lymphedema, menopausal symptoms, and sexual worries develop gradually and persist after curative treatment. These findings can be used to inform clinical practice and facilitate communication and shared decision-making. More research is needed in very early cervical cancer and the impact of fertility sparing therapy on PROs.

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

BackgroundCervical cancer is the sixth most common cancer in Chinese women. A standard treatment modality 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 radiotherapy plus concurrent chemotherapy.MethodsWe 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 chemotherapy. All patients were followed up. Using an actuarial analysis, patient outcomes and treatment-related adverse effects were evaluated and compared.ResultsThe 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 of 4.0 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.ConclusionFor 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.

Rosiglitazone enhances radiosensitivity by inhibiting repair of DNA damage in cervical cancer cells.

Radiation therapy (RT) is one of the main treatment modalities for cervical cancer. Rosiglitazone (ROSI) has been reported to have antiproliferative effects against various types of cancer cells and also to induce antioxidant enzymes that can scavenge reactive oxygen species (ROS) and thereby modify radiosensitivity. Here, we explored the effect of ROSI on radiosensitivity and the underlying mechanisms in cervical cancer cells. Three cervical cancer cell lines (ME-180, HeLa, and SiHa) were used. The cells were pretreated with ROSI and then irradiated. Expression of proteins of interest was detected by western blot and immunofluorescence. Intracellular production of ROS was measured by H2DCFDA. Radiosensitivity was assessed by monitoring clonogenic survival. Expression of antioxidant enzymes (catalase, superoxide dismutases) was increased by ROSI in HeLa and SiHa cells, but not in ME-180 cells. With ROSI pre-treatment, cell survival after irradiation remained unchanged in HeLa and SiHa cells, but decreased in ME-180 cells. Radiation-induced expression of γ-H2AX was increased and that of RAD51 was decreased by ROSI pre-treatment in ME-180 cells, but not in HeLa cells. ROSI increases radiosensitivity by inhibiting RAD51-mediated repair of DNA damage in some cervical cancer cell lines; therefore, ROSI is a potential inhibitor of RAD51 that can be used to enhance the effect of RT in the treatment of some cervical cancers.

Portfolio of prospective clinical trials including brachytherapy: an analysis of the ClinicalTrials.gov database.

BackgroundTo evaluate the current status of prospective interventional clinical trials that includes brachytherapy (BT) procedures.MethodsThe records of 175,538 (100 %) clinical trials registered at ClinicalTrials.gov were downloaded on September 2014 and a database was established. Trials using BT as an intervention were identified for further analyses. The selected trials were manually categorized according to indication(s), BT source, applied dose rate, primary sponsor type, location, protocol initiator and funding source. We analyzed trials across 8 available trial protocol elements registered within the database.ResultsIn total 245 clinical trials were identified, 147 with BT as primary investigated treatment modality and 98 that included BT as an optional treatment component or as part of the standard treatment. Academic centers were the most frequent protocol initiators in trials where BT was the primary investigational treatment modality (p < 0.01). High dose rate (HDR) BT was the most frequently investigated type of BT dose rate (46.3 %) followed by low dose rate (LDR) (42.0 %). Prostate was the most frequently investigated tumor entity in trials with BT as the primary treatment modality (40.1 %) followed by breast cancer (17.0 %). BT was rarely the primary investigated treatment modality for cervical cancer (6.8 %).ConclusionMost clinical trials using BT are predominantly in early phases, investigator-initiated and with low accrual numbers. Current investigational activities that include BT mainly focus on prostate and breast cancers. Important questions concerning the optimal usage of BT will not be answered in the near future.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0624-8) contains supplementary material, which is available to authorized users.

Low-Dose-Rate Brachytherapy Boosting Concurrent Chemoradiation as a Definitive Treatment Modality for Cervical Cancer

To review and report the long-term treatment-induced adverse events (AEs) and outcomes of concomitant chemoradiotherapy boosted by low-dose-rate (LDR) conventional brachytherapy (BT) planning in patients with locoregionally advanced cervical cancer. After obtaining institutional review board approval, we reviewed the records of patients with stage IB1 to IVA, intact cervical cancer who were treated at our institution between 1983 and 2009. Eligible patients underwent definitive radiotherapy with external-beam radiation concomitant with cisplatin-based chemotherapy and boosted by LDR BT. Patient, tumor, and treatment characteristics; treatment-induced AEs, namely, gastrointestinal and genitourinary toxicities, as well as treatment outcomes; locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were reviewed and reported. The study included 129 eligible cervical cancer patients; the median age was 46 years (mean, 47 ± 11 y; range, 28 to 81 y), consisting of stages I, II, III, and IV (29.5%, 48.1%, 17.8%, and 4.6%, respectively). The median follow-up was 37 months (mean, 58 ± 59 mo; range, 3 to 275 mo). The 3-year OS, PFS, LRC, and DC were 75.9%, 71.6%, 84.7%, and 80.2%, respectively. The 5-year OS, PFS, LRC, and DC were 70.7%, 68.7%, 84.7%, and 78.3%, respectively. The 10-year OS, PFS, LRC, and DC were 68.7%, 62.3%, 82.5%, and 73.2%, respectively. Gastrointestinal and genitourinary grade 3 and 4 acute AEs were reported in 3.9% and 0%, and chronic grade 3 and 4 AEs were reported in 20.9% and 12.4% of all patients, respectively. Definitive chemoradiotherapy followed by conventional LDR BT boost is effective, feasible, and tolerable treatment modality for cervical cancer. A comparison with MRI image-guided BT shows comparable treatment outcomes with superior OS in favor of LDR BT but inferior LC with a relatively worse toxicity profile.

Clinical outcomes of primary surgical treatment for acquired vulvar lymphangioma circumscriptum

ObjectiveTo assess the clinical outcomes of surgical treatment for acquired vulvar lymphangioma circumscriptum in patients who received radical surgery and/or adjuvant radiation therapy for cervical cancer.MethodsA retrospective chart review of eight patients was performed to assess the demographic information, chief complaints, treatment modality for cervical cancer, location, and primary treatment modality for vulvar LC, postoperative changes in symptoms, and/or signs, the development of local recurrence and the outcome of patients.ResultsAll eight patients were previously diagnosed with cervical cancer FIGO clinical stage IA to IIA and received surgery, radiation therapy, or concurrent chemoradiation therapy. Microscopic examination revealed multiple, dilated, D2-40-positive dermal vascular channels containing eosinophilic proteinaceous material, consistent with LC. Most chief complaints showed considerable improvements on assessment at the outpatient clinic after the primary surgery. No patient showed aggravation of symptoms. Two patients developed local recurrences. One patient developed recurrence on the opposite side 13 months after local excision. We performed a second wide local excision. Another patient developed recurrence 47 months after the primary surgery. Since the lesion was very small and localized, we decided to manage it conservatively, but monitor it very closely. The remaining six patients remained free of recurrence.ConclusionIt is not easy for gynecologists to have an initial clinical diagnosis of LC, because there are a number of diseases that exhibit similar clinical manifestation to that of vulvar LC. Even if it is diagnosed correctly, local recurrence often occurs. Relevant symptoms associated with LC are not only distressing, but also affect patients’ quality of life. Based on our data, we propose that surgical treatment could provide a more long-lasting answer compared to other treatment modalities, since it is beneficial in terms of clinical outcomes. In the future, a long-term follow-up investigation is required to assess the prognosis and to compare the efficacy and side effects of each modality.

Antitumor effect of photodynamic therapy with a novel targeted photosensitizer on cervical carcinoma.

The antitumor effect of photodynamic therapy (PDT) mediated by a novel photosensitizer I (Ps I; {γ-[N-poly(ethyleneglycol)]folic acid}-5,10,15-tris(3-hydroxyphenyl)-20-(4-carboxyphenyl)chlorin), in which chlorin was used as a photoactive unit, folic acid as a tumor‑targeting warhead, and polyethylene glycol as a linker, on cervical carcinoma was studied in vitro and in vivo. Ps I exhibited a considerably higher cellular uptake by HeLa cells than folic acid-free analogue Ps A (tert-butyl N-poly(ethyleneglycol)ethylcarbamate-5,10,15-tris(3-hydroxyphenyl)-20-(4-carboxyphenyl)chlorin), and the cellular uptake by HeLa cells of Ps I could be competitively inhibited by excess folic acid. Moreover, at different time points after the intravenous (i.v.) injection of Ps I and A, Ps I produced a >2-fold higher tumor to normal tissue ratio in tumor-bearing nude mice as compared to Ps A. MTT assay indicated that the HeLa cell proliferation inhibition ratio was increased 34% after Ps I-PDT compared with Ps A-PDT with a photosensitizer concentration of 15.2 µmol/l. Administration of Ps I (7 mg/kg, i.v.) followed by light exposure (80 J/cm2) markedly suppressed the growth of xenograft tumors, and the tumor volume was 10-fold smaller than that of the control group. Tumor growth inhibition in vitro and in vivo had an obvious dependency on the Ps I concentration and irradiation dose. The mode of cell death post-Ps I-PDT was analyzed by flow cytometry, confocal laser scanning microscopy, and electron microscope, and the results suggested that apoptosis was the primary mode of HeLa cell death induced by Ps I-PDT. The results also demonstrated that tumor targeting of Ps I was clearly improved because of the endocytosis mediated by the folate receptor. As a result, Ps I-PDT exhibited higher antitumor activity than Ps A-PDT and has potential as an alternative treatment modality for cervical cancer.

Abstract 2753: Ormeloxifene inhibits cervical cancer cell growth through intrinsic apoptotic pathway

Abstract Background: Cervical cancer (CxCa) remains the fourth leading cause of cancer related death among women worldwide. Cervical cancer is mainly (∼ 99.7%) derived from high risk Human papillomavirus (HR HPV). HPV E6/E7 oncoproteins interfere with p53 and pRb (retinoblastoma) cell cycle regulatory proteins and hinder their efficacy of controlling cell growth. Advanced stage cervical cancer is difficult to treat and patients diagnosed with metastatic disease have a poor survival rate of only 16%. Therefore, there is an urgent need to develop newer treatment modalities. Ormeloxifene is a non-hormonal, anti-estrogen, oral contraceptive for human use that effectively suppresses the proliferation of decidual cells in the endometrium to inhibit egg implantation. Growing evidences also suggest that ormeloxifene has anti-cancerous properties in breast, head and neck, and chronic myeloid leukemia cancers. Hence, considering its strong anti-proliferative/cancerous effect, we hypothesized that ormeloxifene may also inhibit the growth of cervical cancer cells and may suppress the expression of E6 and E7 HPV oncoproteins. Methods: We performed in vitro anti-cancer studies with ormeloxifene (dose range: 5 µM to 25 µM) in the HPV positive cervical cancer cell lines (Caski and SiHa) by utilizing MTS and colony formation assays. To further determine the effects of ormeloxifene on the cellular and molecular level, immunoblotting, flow cytometry and real time PCR analyses were performed using the Caski cell line model. Results: Ormeloxifene effectively inhibited cervical cancer cell growth as determined by proliferation and colony formation assays in a dose dependent manner. Ormeloxifene decreased mitochondrial membrane potential and induced apoptosis as shown by flow cytometry analysis of cells stained with TMRE (tetramethylrhodamine, ethyl ester) and 7AAD/Annexin V, respectively. Apoptosis was also confirmed by immunoblotting for cleaved PARP (Poly ADP ribose polymerase), Caspase 3 and Caspase 9. Additionally, ormeloxifene treatment arrested cell cycle in G1-S transition and decreased the expression of p-Akt while total Akt remained the same. Specifically relevant to cervical cancer, ormeloxifene decreased the expression of HPV E6/E7 at mRNA and protein levels as determined by quantitative PCR analysis and immunoblotting, respectively. Interestingly, ormeloxifene restored the levels of p53, Rb and PTPN 13 (Protein tyrosine Phosphatase non receptor type 13) tumor suppressor proteins as shown by immunoblotting. Conclusion: Our findings suggest that ormeloxifene inhibits cervical cancer cell growth and decreases mitochondrial membrane potential which clearly demonstrates that apoptosis is induced via intrinsic pathway. Importantly, ormeloxifene downregulates the expression of HPV E6/E7 oncoproteins. Thus, ormeloxifene appears to be a novel treatment modality for cervical cancer. Citation Format: Neeraj Chauhan, Mohd S. Zaman, Murali M. Yallapu, Diane M. Maher, Mara C. Ebeling, Subhash C. Chauhan, Meena Jaggi. Ormeloxifene inhibits cervical cancer cell growth through intrinsic apoptotic pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2753. doi:10.1158/1538-7445.AM2014-2753

Comparisons of 5-aminolevulinic acid photodynamic therapy and after-loading radiotherapy in vivo in cervical cancer

To compare the differences between 5-aminolevulinic acid photodynamic therapy (5-ALA-PDT) with traditional after-loading radiotherapy in aspects of efficacies and side effects. MTT assay was adopted to detect the inhibitive effects of 5-ALA-PDT on Hela cells proliferation. Flow cytometry was used to analyze cell apoptosis. After establishment of human cervical cancer xenograft model, the comparisons between 5-ALA-PDT with radiotherapy were performed with respect to treatment efficacies (survival rate, body weight, and tumor volume) and side effects (appearance and behavior, ovarian endocrine functions, and skin lesion around the tumor). 5-Aminolevulinic acid photodynamic therapy exerted killing effects on cervical cancer cells. Morphological changes and flow cytometric analyses indicated apoptosis to be one of the mechanisms for tumor growth suppression. Both proliferation inhibition and cell apoptosis showed dependency on photosensitizer concentration and irradiation intensity. Repeated photodynamic therapy presented stronger inhibitive effects on tumor growth compared to after-loading radiotherapy, while producing milder impairment of ovarian endocrine functions and skin lesions around the tumors. 5-Aminolevulinic acid photodynamic therapy has great potential to be an alternative treatment modality for cervical cancer.

Profiling Protein Markers Associated with the Sensitivity to Concurrent Chemoradiotherapy in Human Cervical Carcinoma

Concurrent chemoradiotherapy (CCRT) is recently recommended as the primary and standard treatment modality for cervical cancer. The aim of this study is to investigate the protein biomarkers associated with CCRT sensitivity, so as to better understand the mechanisms underlying CCRT resistance. Fresh tumor tissues from five cases for each group of CCRT-highly sensitive (CCRT-HS) and CCRT-lowly sensitive (CCRT-LS) were analyzed by 2-D electrophoresis coupled with MALDI-TOF-MS, followed by Western blot for four candidate proteins including S100A9, galectin-7, nuclear matrix protein-238 (NMP-238), and heat shock protein-70 (HSP-70). In randomly selected CCRT-HS (n = 60) and CCRT-LS (n = 35) cases, these four differentially expressed proteins were detected by tissue microarray with immunohistochemistry staining to explore the association between these interested proteins and CCRT sensitivity. Nineteen proteins differentially expressed more than four times between two groups were identified. An association was revealed between CCRT sensitivity and increased S100A9 and galectin-7, but decreased NMP-238 and HSP-70 expression (p < 0.001, respectively). Although none of these four protein markers could be used as an independent predictive factor, a recurrence prediction model was generated by combining S100A9, galectin-7, NMP-238, and HSP-70 as a full predictive factor. The proteomic analysis combined with tissue microarray provides us a dramatic tool in predicting CCRT response. The increased expression of S100A9 and galectin-7, but decreased expression of NMP-238 and HSP-70, suggests a significantly increased sensitivity to CCRT in cervical cancer.

Radiation therapy of cervical cancer: Current status in Korea and recent developments

Brachytherapy is an essential part of the radiotherapy for uterine cervical cancer. Since 1979, high dose rate (HDR) brachytherapy has been used for the treatment of uterine cervical cancer in Korea; the number of institutions employing HDR has been increasing. At 40 radiation oncology departments out of 53 in Korea, HDR brachytherapy was practiced in 2004. Approximately in 1,000 of patients, brachytherapy was done annually and among these, HDR proportions were 75-80%. In Korea, treatment results for HDR are comparable with the low dose rate (LDR) system series and appear to be a safe and effective alternative to LDR for the treatment of cervical carcinoma. The studies from the major centers report the five-year survival rate of cervical cancer as, 78-86% for Stage I, 68-85% for stage II, and 38-56% for Stage III. In conclusion, HDR intracavitary radiotherapy is increasingly practiced in Korea and an effective treatment modality for cervical cancer. To determine the optimum radiation dose and fractionation schedule, a nation-wide prospective study is necessary in Korea. Recently a three-dimensional conformal radiotherapy (3DCRT) or an intensity-modulated radiotherapy (IMRT), which allow for a high degree of conformity to the target volume have been used for the uterine cervical cancer. Several studies have reported the superiority of IMRT, over the conventional technique, in reducing the small bowel dose. The author will introduce the small bowel displacement system (SBDS)-assisted IMRT for cervical cancer patients. Positional changes of the uterus during radiotherapy, which can degrade the accuracy of 3DCRT and IMRT, will be discussed.