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Friday, September 16, 2016 3:40 AM| Basu P, Jenson AB, Majhi T, Choudhury P, Mandal R, Banerjee D, Biswas J, Pan J, Rai SN, Ghim SJ, Miller D|IARC Scientific Papers|Labels: RXR, cervical cancer, clinical trial

Phase 2 Randomized Controlled Trial of Radiation Therapy Plus Concurrent Interferon-Alpha and Retinoic Acid Versus Cisplatin for Stage III Cervical Carcinoma.

Int J Radiat Oncol Biol Phys. 2016 Jan 1;94(1):102-10

Authors: Basu P, Jenson AB, Majhi T, Choudhury P, Mandal R, Banerjee D, Biswas J, Pan J, Rai SN, Ghim SJ, Miller D

Abstract
PURPOSE: Because a combination of retinoic acid, interferon-alpha, and radiation therapy demonstrated synergistic action and effectiveness to treat advanced cervical cancers in earlier studies, we designed this randomized phase 2 open-label trial to assess efficacy and safety of interferon alpha-2b (IFN) and 13-cis-retinoic acid (RA) administered concomitantly with radiation therapy (IFN-RA-radiation) to treat stage III cervical cancer.
METHODS AND MATERIALS: Stage III cervical cancer patients were randomized to study and control groups in a 1:1 ratio. All patients were treated with radiation therapy; study arm patients received IFN (3 × 10(6) IU subcutaneously) 3 times a week for 4 weeks and daily RA (40 mg orally) for 30 days starting on day 1 of radiation, whereas control arm patients received weekly cisplatinum (40 mg/m(2)) for 5 weeks during radiation. Patients were followed for 3 years. The primary endpoint was overall survival at 3 years.
RESULTS: Patients in the study (n=104) and control (n=105) groups were comparable for clinicopathological characteristics, radiation therapy-related variables and treatment response. Proportions of disease-free patients in the study and control groups were 38.5% and 44.8%, respectively, after median follow-up of 29.2 months. Hazard ratios were 0.67 (95% confidence interval [CI]: 0.44-1.01) and 0.69 (95% CI: 0.44-1.06) for overall and disease-fee survival, respectively, comparing the study group to control, and demonstrated an inferior outcome with RA-IFN-radiation, although differences were statistically nonsignificant. Kaplan-Meier curves of disease-free and overall survival probabilities also showed inferior survival in the study group compared to those in the control. Acute toxicities of chemoradiation were significantly higher with 2 acute toxicity-related deaths.
CONCLUSIONS: Treatment with RA-IFN-radiation did not demonstrate survival advantage over chemoradiation despite being less toxic. The trends predicted an inferior outcome with the RA-IFN combination.

PMID: 26700705 [PubMed - indexed for MEDLINE]

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: cervical cancer, clinical trial
RATIONALE: Drugs used in chemotherapy, such as cisplatin, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known whether chemotherapy and radiation therapy are more effective when given with or without additional chemotherapy in treating cervical cancer. PURPOSE: This randomized phase III trial is studying chemotherapy and pelvic radiation therapy to see how well they work when given with or without additional chemotherapy in treating patients with high-risk early-stage cervical cancer after radical hysterectomy.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: cervical cancer, skin cancer, clinical trial
The purpose of this study to investigate the safety and efficacy of using nivolumab to treat subjects who have virus-associated tumors. Certain viruses that infect human cells have been known to play a role in tumor formation and growth. This study will investigate the effects of the study drug nivolumab in human subjects who have the following types of viral-associated tumors: Gastric Cancer, nasopharyngeal carcinoma , cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel Cell Carcinoma.
Wednesday, September 14, 2016 11:10 AM|John P. Geisler, Jayanth Swathirajan, Katherine L. Wood, Kelly J. Manahan|Journal of Cancer|Labels: cervical cancer, cost

Background: Trials have demonstrated improvements in survival with adding paclitaxel (P) or topotecan (T) to cisplatin (C) for the treatment of advanced cervical cancer. We sought to evaluate the cost effectiveness of these regimens.

Methods: A decision model was developed based on Gynecologic Oncology Group (GOG) protocols 169 and 179. Arm 1 is 6 cycles of cisplatin. Arm 2 is 6 cycles of CP while arm 3 is 6 cycles of CT. Parameters include overall survival (OS), cost and complications. Sensitivity analyses were performed.

Results: The incremental cost-effectiveness ratio (ICER) for C versus CP is $13,654/quality-adjusted life-year (QALY) gained. For CT compared to C, the ICER is $152,327/QALY. When compared simultaneously, CT is dominated. At a willingness to pay (WTP) threshold of $50,000/QALY, C is the preferred option but CP is acceptable. Sensitivity analyses suggest that CT would become the preferred option if it was to improve OS to 24 months (compared to 9.4 months).

Conclusions: In this model, CP is an acceptable alternative to cisplatin for the treatment of these patients with an increase in cost of only $13,654/QALY. The addition of topotecan did not increase survival enough to justify the increased cost.

Wednesday, August 31, 2016 11:00 PM|Mabuchi, Seiji; Yokoi, Eriko; Owa, Takao; Kozasa, Katsumi; Yamashita, Michiko; Kobayashi, Eiji; Tomimatsu, Takuji; Yoki, Takeshi; Tsutui, Tateki; Kimura, Tadashi|International Journal of Gynecological Cancer - Current Issue|Labels: cervical cancer, clinical trial
imageObjectives: This study aimed to determine the maximum tolerated dose and acute dose-limiting toxicities (DLTs) of intravenous irinotecan plus oral S-1 in patients with advanced or recurrent uterine cervical cancer. Methods: Irinotecan was administered intravenously over the course of 90 minutes on day 1, and S-1 was given orally in 2 divided doses from days 1 to 14 of a 21-day cycle. The dose of S-1 was escalated in a stepwise fashion from 40 (level 1) to 60 mg/m2 (level 2) and then 80 mg/m2 (level 3), whereas the dosage of irinotecan remained the same (150 mg/m2). The primary end point for the escalation study was acute DLT that occurred within 2 cycles of chemotherapy. Results: Twelve patients were enrolled and treated over 3 dose levels. Their median age was 47 years (range, 28–48 years). At level 1, one episode of grade 3 anemia and a grade 3 fatigue were observed, but no DLT developed. At level 2, the first patient experienced febrile neutropenia, which was considered to be a DLT. To evaluate the toxicity of this dose level, 5 more patients were evaluated. However, no DLT developed in these patients. At level 3, although grade 1 to 2 hematological and nonhematological toxicities developed, no DLT occurred. Conclusions: In women with advanced or recurrent cervical cancer previously treated with platinum-based chemotherapy, S-1 plus irinotecan in a triweekly setting is a reasonable treatment regimen with an acceptable toxicity profile. The recommended doses of S-1 and irinotecan for this regimen are 80 and 150 mg/m2, respectively.
Wednesday, August 31, 2016 11:00 PM|Usami, Tomoka; Takahashi, Akimasa; Matoda, Maki; Okamoto, Sanshiro; Kondo, Eiji; Kanao, Hiroyuki; Umayahara, Kenji; Takeshima, Nobuhiro|International Journal of Gynecological Cancer - Current Issue|Labels: cervical cancer
imageObjectives: In most patients, stage IVB cervical cancer is incurable, and the outcomes are poor. There is significant individual variation in patients with stage IVB cervical cancer, in whom standard treatment has not been well defined. This study aims to review the outcomes and discuss treatment strategies in patients with stage IVB cervical cancer. Methods: From January 1, 1992, to December 31, 2011, we retrospectively reviewed the data of patients with stage IVB cervical cancer who were given a diagnosis at the Department of Gynecology of the Cancer Institute Hospital. Results: A total of 111 patients were enrolled. At the time of analysis, the median overall survival (OS) was 16.6 months (range, 0.2–120.9 months), and the 5-year OS rate was 20.2%. The 5-year OS rate was 59.4% for those with only para-aortic lymph node metastases; 24.8% for those with lymphogenous metastases, excluding those with only para-aortic lymph node metastases; 6.1% for those with hematogenous metastases; and 0% for those with disseminated metastases. The OS in patients with lymphogenous metastases was better compared with that of those with either hematogenous or disseminated metastases (P < 0.0001). In multivariate analysis, the performance status, site of metastases (only lymph node or other metastases), and local stage were all independent prognostic factors. Conclusions: We determined performance status, site of metastases (only lymph node or other metastases), and local stage as independent prognostic factors in patients with stage IVB cervical cancer. Regarding treatment, we confirmed that the effectiveness of chemotherapy was also of significance.
Sunday, August 14, 2016 10:05 PM|Tyagi, A., Vishnoi, K., Mahata, S., Verma, G., Srivastava, Y., Masaldan, S., Roy, B. G., Bharti, A. C., Das, B. C.|Clinical Cancer Research recent issues|Labels: cervical cancer

Purpose: Perturbation of keratinocyte differentiation by E6/E7 oncoproteins of high-risk human papillomaviruses that drive oncogenic transformation of cells in squamocolumnar junction of the uterine cervix may confer "stem-cell like" characteristics. However, the crosstalk between E6/E7 and stem cell signaling during cervical carcinogenesis is not well understood. We therefore examined the role of viral oncoproteins in stem cell signaling and maintenance of stemness in cervical cancer.

Experimental Design: Isolation and enrichment of cervical cancer stem–like cells (CaCxSLCs) was done from cervical primary tumors and cancer cell lines by novel sequential gating using a set of functional and phenotypic markers (ABCG2, CD49f, CD71, CD133) in defined conditioned media for assessing sphere formation and expression of self-renewal and stemness markers by FACS, confocal microscopy, and qRT-PCR. Differential expression level and DNA-binding activity of Notch1 and its downstream targets in CaCxSLCs as well as silencing of HPVE6/Hes1 by siRNA was evaluated by gel retardation assay, FACS, immunoblotting, and qRT-PCR followed by in silico and in vivo xenograft analysis.

Results: CaCxSLCs showed spheroid-forming ability, expressed self-renewal and stemness markers Oct4, Sox2, Nanog, Lrig1, and CD133, and selectively overexpressed E6 and HES1 transcripts in both cervical primary tumors and cancer cell lines. The enriched CaCxSLCs were highly tumorigenic and did recapitulate primary tumor histology in nude mice. siRNA silencing of HPVE6 or Hes1 abolished sphere formation, downregulated AP-1-STAT3 signaling, and induced redifferentiation.

Conclusions: Our findings suggest the possible mechanism by which HPVE6 potentially regulate and maintain stem-like cancer cells through Hes1. Clin Cancer Res; 22(16); 4170–84. ©2016 AACR.

Monday, August 8, 2016 10:39 AM|Mei, Q., Li, X., Zhang, K., Wu, Z., Li, X., Meng, Y., Guo, M., Luo, G., Fu, X., Han, W.|Clinical Cancer Research Online First Articles|Labels: AKT, PI3K, cervical cancer

Purpose: Loss of Chr9q31-33 is one of the most common chromosome imbalances of cervical cancer, but the underlying mechanism has not been well documented. Experimental Design: The loss of heterozygosity (LOH) status of Chr9q31-33 was investigated utilizing 26 microsatellite markers. We detected the expression of miR-181a2/181b2 by qRT-PCR analysis of cervical cancer cell lines and 100 paired tumor samples and corresponding adjacent non-tumor tissues. Kaplan-Meier and Cox proportional hazard regression analysis were performed to identify the prognostic value of miR-181a2/181b2. Regulation of expression was analyzed by methylation-specific PCR. The tumor suppressing effects of miR-181a2/181b2 were determined in vitro and in vivo. The target gene and signaling pathway mediated the function of miR-181a2/181b2 were also identified. Results: Chr9q33.3 was identified as one of the most deleted regions in cervical cancer. Under-expression of miR-181a2/181b2 was detected in 46% of cervical caner, and was induced by LOH of chr9q33.3 and promoter hypermethylation. Attenuated miR-181a2/181b2 expression predicted a poor prognostic phenotype and advanced clinical stage of cervical cancer. miR-181a2/181b2 prominently dampened cell cycle progression, suppressed cell growth and promoted apoptosis of tumor cells in vitro. They also effectively impeded tumor formation and growth in vivo. miR-181a2/181b2 exert the tumor suppressor ability by depressing direct target PIK3R3 (p55) and consequently modulating PIK3R3/Akt/FoxO signaling pathway. Conclusions: We demonstrated a cause-and-effect event beginning from loss of chr9q33.3, a frequent event in cervical cancer, to the under-expression of miR-181a2/181b2, leading to the elevated activation of PI3K pathway.

Monday, June 27, 2016 10:52 AM|OISHI, S., KUDAKA, W., TOITA, T., ARIGA, T., NAKAMOTO, T., WAKAYAMA, A., NAGAI, Y., KANESHIMA, I., NISHIHIRA, K., AOKI, Y.|Anticancer Research recent issues|Labels: cervical cancer, clinical trial

Aim: We report a retrospective evaluation for patients with stage IVB cervical cancer in order to identify survival rates and to improve our current practice. Patients and Methods: We analyzed 85 patients with stage IVB cervical cancer. For patients appropriate for radical treatment, a combination of external-beam radiotherapy and intracavitary brachytherapy was delivered with/without chemotherapy. Patients with distant metastasis were treated using systemic chemotherapy or palliative radiotherapy. Results: Forty-two patients were treated using radiotherapy alone, 31 using chemotherapy followed by radiotherapy, eight using chemotherapy alone, and four using best supportive care. The 5-year overall survival rate was 9.9%. Multivariate analysis revealed leukocytosis and a poor performance status were independent prognostic factors. Of the 43 patients without these prognostic factors, patients with only lymph node metastasis had a 5-year overall survival rate of 40.5%. Conclusion: Radical treatment should be considered in patients who have only lymph rode metastasis and are without leukocytosis and a poor performance status.

Monday, June 6, 2016 4:58 AM|NAKAMURA, K., NAKAYAMA, K., ISHIKAWA, M., KATAGIRI, H., MINAMOTO, T., ISHIBASHI, T., ISHIKAWA, N., SATO, E., SANUKI, K., YAMASHITA, H., KOMATSU-FUJII, T., KYO, S.|Anticancer Research recent issues|Labels: CEA, cervical cancer

Background/Aim: We aimed to evaluate the prognostic significance of high pre-treatment plasma D-dimer levels in patients with cervical carcinoma (CC) after adjusting for venous thromboembolism. Patients and Methods: Relationships between the clinicopathological characteristics and the overall (OS) and progression-free (PFS) survival rates of patients with CC (N=129) were examined. Survival was calculated using the Kaplan–Meier method and prognostic indicators assessed using a Cox proportional hazards model. Results: A high pre-treatment plasma level of D-dimers, detected in 42.6% of cases (N=55), was associated with advanced tumour stage. In the multivariate analysis, high pre-treatment plasma D-dimer levels, tumour stage, histological type, and carcinoembryonic antigen (CEA) levels were identified as independent prognostic factors for OS, while tumour stage and CEA levels were identified as independent prognostic factors for PFS. Conclusion: A high pre-treatment plasma level of D-dimers represents an independent prognostic biomarker for CC that could assist in identifying high-risk populations for treatment decisions.

Thursday, April 28, 2016 9:59 AM|ORYWAL, K., JELSKI, W., ZDRODOWSKI, M., SZMITKOWSKI, M.|Anticancer Research recent issues|Labels: cervical cancer, biomarker diagnostic

Aim: The aim of this study was to investigate a potential role of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) as tumor markers for cervical cancer. Materials and Methods: Blood samples were obtained from 43 women with cervical cancer. Isoenzymes class III, IV of ADH and total ADH activity were measured in the sera by the photometric method and class I, II ADH and ALDH activity by the fluorometric method. Results: The total activity of ADH and ADH I was significantly higher in the serum of patients with cervical cancer than in control groups. The diagnostic sensitivity for ADH I was 61,76%, specificity 65,7%, PPV and NPV were 70 and 62,16% respectively. AUC for ADH I was 0,654 and for total ADH 0,618. Conclusion: The results suggest a potential role of ADH I as a marker for cervical cancer.

Monday, March 14, 2016 8:00 AM|Pediatric News|MedWorm: Vaccines|Comments|Labels: cervical cancer
Full or partial vaccination with the quadrivalent human papillomavirus vaccine reduced the overall risk of abnormal cervical pathology by 36%, based on data from a retrospective cohort study of just... (Source: Pediatric News)

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Monday, February 29, 2016 4:00 PM|Neoplasma|MedWorm: Cancer Therapy|Comments|Labels: P53, cervical cancer
This study revealed that uc.206 is significantly up-regulated in cervical cancer (CC) tissue and negatively correlates with the expression of the pro-apoptotic gene P53 in RNA level. We show that uc.206 specifically targets the 3' untranslated region (3'UTR) of P53 and regulates its expression. Inhibition of uc.206 effectively delays cervical cells proliferation and promotes apoptosis, accompanied by increased expression of P53 protein. Thus, these findings suggested that uc.206 acts as a novel oncogene by targeting the P53 gene and promoting CC cell growth, which might be beneficial for cervical cancer therapy. PMID: 26925787 [PubMed - as supplied by publisher] (Source: Neoplasma)
Sunday, January 24, 2016 5:10 AM|Oncology Research|MedWorm: Cancer Therapy|Comments|Labels: cervical cancer
This study indicates that legumain might play an important role in cervical cancer cell migration and invasion. Legumain might be a potential therapeutic target for cervical cancer therapy. PMID: 26802645 [PubMed - as supplied by publisher] (Source: Oncology Research)