Uterine Cervical Carcinoma Patients Research Articles

Pre-treatment Serum HE4 Level as a Novel Independent Prognostic Biomarker for Uterine Cervical Carcinoma Patients.

In spite of the effective implementation of screening programs, uterine cervical carcinoma (UCC) remains one of the major causes of cancer death among women around the world. The aim of this study was to investigate the prognostic value of serum human epididymis protein 4 (HE4) in UCC. Pre-treatment serum samples from 109 UCC patients and 99 healthy women were analyzed for HE4 levels by a quantitative chemiluminescent microparticle immunoassay on the automated ARCHITECT instrument. HE4 serum (sHE4) levels were significantly higher in UCC patients, regardless of tumor stage, compared with healthy controls. Elevated sHE4 levels were significantly associated with advanced FIGO stage and absence of disease-free interval after treatment. In univariable analysis, higher sHE4 levels were significantly correlated with shorter overall survival and progression-free survival. In multivariable analysis, sHE4 retained its significance as independent adverse prognostic factor for both survival endpoints. This study indicates that sHE4 is associated with a more aggressive tumor phenotype and a worse patient's prognosis. These results suggest the potential role of sHE4 as a novel prognostic marker and as an indicator of high-risk UCC patients for a tailored surgical and adjuvant therapy.

Expression of serum amyloid A in uterine cervical cancer

BackgroundAs an acute-phase protein, serum amyloid A (SAA) is expressed primarily in the liver. However, its expression in extrahepatic tissues, especially in tumor tissues, was also demonstrated recently. In our study, we investigated the expression of SAA in uterine cervical carcinomas, and our results suggested its potential as a serum biomarker.MethodsQuantitative real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the SAA gene and protein expression levels in the tissues and sera of patients with non-neoplastic lesions (NNLs), cervical intraepithelial neoplasia (CIN) and cervical carcinoma (CC).ResultsCompared with NNLs, the SAA gene (SAA1 and SAA4) expression levels were significantly higher in uterine CC (mean copy numbers: 138.7 vs. 5.01, P < 0.000; and 1.8 vs. 0.079, P = 0.001, respectively) by real-time PCR. IHC revealed cytoplasmic SAA protein staining in tissues from adenocarcinoma and squamous cell carcinoma of the cervix. The median serum concentrations (μg/ml) of SAA were 6.02 in patients with NNLs and 10.98 in patients with CIN (P = 0.31). In contrast, the median serum SAA concentration was 23.7 μg/ml in uterine CC patients, which was significantly higher than the SAA concentrations of the NNL group (P = 0.002) and the CIN group (P = 0.024).ConclusionsOur data suggested that SAA might be a uterine CC cell product. High SAA concentrations in the serum of CC patients may have a role in monitoring disease occurrence and could have therapeutic applications.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1433263219102962.

Expression of Bmi-1, P16, and CD44v6 in Uterine Cervical Carcinoma and Its Clinical Significance.

ObjectiveBmi-1, a putative proto-oncogene, is a core member of the polycomb gene family, which is expressed in many human tumors. The p16 protein negatively regulated cell proliferation, whereas CD44v6 is associated with proliferation as an important protein. Additionally, CD44v6 is an important nuclear antigen closely correlated to tumor metastasis. The present study aims to investigate the expression and significance of Bmi-1, p16, and CD44v6 in uterine cervical carcinoma (UCC).MethodsA total of 62 UCC, 30 cervical neoplasic, and 20 normal cervical mucosal tissues were used in the current study. The expression of Bmi-1, p16, and CD44v6 in these tissues was determined using immunohistochemical assay. The relationships among the expression of these indices, the clinicopathologic features of UCC, and the survival rate of UCC patients were also discussed. The correlation between Bmi-1 protein expression and p16 or CD44v6 protein in UCC was analyzed.ResultsThe expression of Bmi-1, p16, and CD44v6 was significantly high in cervical carcinoma compared with that in the cervical neoplasia and normal colorectal mucosa (P<0.05). The over-expression of Bmi-1 protein in UCC was apparently related to the distant metastasis (P<0.01) and the tumor, nodes and metastasis-classification, i.e. the TNM staging, World Health Organization (P<0.05). Nevertheless, the positive expression of p16 protein in UCC was not significantly associated with the clinicopathologic features (P>0.05). The Kaplan–Meier survival analysis showed that the over-expression of Bmi-1 significantly decreased the survival rate of UCC patients (P<0.05). A strong correlation indicated that there was statistical significance between the expression of Bmi-1 and CD44V6 proteins in UCC (r=0.419, P=0.001).ConclusionsThe over-expression of Bmi-1 and CD44v6 protein closely correlate to the tumorigenesis, metastasis, and prognosis of UCC. Bmi-1 and CD44v6 may be used to predict the prognosis of cervical carcinoma. Bmi-1 may indirectly regulate the expression of CD44v6 in UCC patients. The positive expression of p16 protein is possibly associated with the tumorigenesis, but not with the metastasis or prognosis of UCC.

Pretreatment tumor diameter/volume and pelvic lymph node status assessed by magnetic resonance imaging for uterine cervical carcinoma treated with concurrent chemotherapy and radiotherapy

The aim is to evaluate the prognostic value of tumor diameter, volume and pelvic lymph node status assessed by magnetic resonance imaging (MRI) in patients with uterine cervical carcinoma patients treated with concurrent chemotherapy and radiotherapy. Ninety-eight patients diagnosed with stage IB to IIIB cervical carcinoma were entered into the study. Tumor diameter was evaluated in T2-weighted image. The tumor volume was calculated by the equation (volume = width x length x height x pi/6) as an ellipsoid approximation. Univariate and multivariate analyses were performed to identify the prognostic factors for overall survival (OS), disease-free survival (DFS), pelvic control (PC) and distant metastasis-free survival (DMFS). The 5-year OS, DFS, PC and DMFS rate were 59.8%, 57.3%, 67.9% and 78.8%, respectively. Using univariate analyses, large MRI tumor diameter (4 cm), large tumor volume (30 mL), pelvic enlarged pelvic lymph nodes, large clinical diameter (4 cm) and International Federation of Gynecology and Obstetrics (FigO) stage showed a statistically significantly unfavorable influence on OS and DFS. In multivariate analyses, large tumor volume affected OS, DFS, PC and DMFS, and enlarged pelvic lymph nodes also affected OS. Tumor volume and enlarged pelvic lymph nodes determined by pretreatment MRI examinations were significant prognostic factors for patients with invasive cervical carcinoma treated with concurrent chemotherapy and radiotherapy.

Multi-institutional study of radiation therapy for isolated para-aortic lymph node recurrence in uterine cervical carcinoma: 84 subjects of a population of more than 5,000

Most patients who had any recurrent sites of cancer have been considered to be in their last stage of life. However, recent advances of clinical research reveal some patients achieve long-term survival even in recurrence. Furthermore, for patients who had only one recurrent region, radiation therapy could play an important role. As for uterine cervical carcinoma, the most common recurrent site other than the pelvis is the para-aortic lymph nodes. Thus we conducted the current study. Between 1994 and 2003, more than 5,000 uterine cervical carcinoma patients were treated with curative intended treatments at 13 Japanese hospitals. Of these patients, 84 developed para-aortic lymph node recurrence as the only site of initial tumor progression. These patients were treated with external beam radiation therapy. Radiation therapy protocol was as follows: 1.7-2.0 Gy per fraction, 5 fractions per week, and the mean total dose was 50.8 Gy (25-60 Gy). Three- and 5-year overall survival rates of all patients were 49.5% and 31.3%, respectively. Stratified by symptom sign, 3-year overall survival rate of symptom positive was 27.6% and those of the negative was 56.1% (p = 0.018). Three-year overall survival rates of the total dose > or =51 Gy and that of < or =50 Gy were 58.0% and 42.8%, respectively (p = 0.07). As for morbidity, no patients received Grade 3 or greater late toxicity. The current study suggested that radiation therapy for isolated para-aortic lymph node recurrence in uterine cervical carcinoma could have a significant impact on survival.

A multi-institutional study of radiation therapy for isolated para-aortic lymph node recurrence in uterine cervical carcinoma: 84 subjects out of over 5,000 population

5052 Background: Most patient who had any recurrent sites of cancer, have been considered to be last-stage of life. However, recent advances of clinical research reveal some patients achieve long-term survival even in recurrence cases. Furthermore, patients who had only one recurrent region, even radiation therapy could play an important role. As for uterine cervical carcinoma, the most common recurrent site other than pelvis is para-aortic lymph node. Furthermore, improvement of diagnostic imaging enables us to detect more frequently isolated para-aortic lymph node recurrence. Thus, we conducted the current study. Methods: Between 1994 and 2003, over 5000 uterine cervical carcinoma patients treated with curative intended treatments at sixteen Japanese major hospitals. Out of them, 84 patients developed para-arotic lymph node recurrence as the only site of initial tumor progression. Seventy-four patitents had squamous cell carcinoma and 5 had adenosquamous cell carcinoma and 5 had adenocarcinoma. These patients were treated with external beam radiation therapy prescribing 1.7–2.0 Gy per fraction, 5 fractions per week and median total dose was 50 Gy (25–60 Gy). Thirty-two patients received adjuvant systemic chemotherapy. Results: Median follow-up time of all patients was 20 months (2–92 months). Three- and 5-year overall survival rates of all patients were 49.5% and 31.3%, respectively. Stratified by patients with or without chemotherapy, 3-year overall survival rate of patients with chemotherapy group was 37.7% and those without group was 56.7% (p = 0.69). Moreover, stratified by symptom sign, 3-year overall survival rate of symptom positive group was 27.6% and those of negative group was 56.1% (p = 0.018). Three-year overall survival rates of the total dose ≥ 51Gy and that of ≤ 50 Gy were 58.0% and 42.8%, respectively (p = 0.07). AS for morbidity, no patients received G3 or greater late toxicity (CTCAE ver. 3.0). Conclusions: The current study suggested that radiation therapy for isolated para-aortic lymph node recurrence in uterine cervical carcinoma could have significant impact on overall survival. Furthermore, no symptom group and over 51Gy irradiation group could achieve better prognosis. No significant financial relationships to disclose.

Human papillomavirus prevalence in postradiotherapy uterine cervical carcinoma patients: correlation with recurrence of the disease

To understand the role of human papillomavirus (HPV) in recurrence of uterine cervical cancer (CA-CX) after radiotherapy, we have analyzed the HPV prevalence in the exfoliated cells of 56 patients and their corresponding plasma. HPV DNA was detected in exfoliated cells of 78% (44/56) patients (HPV-16, 68%; HPV-18, 14%; HPV-X [other than 16, 18], 11%; and mixed infection of HPV-16 and HPV-18 in three cases). HPV DNA in plasma was present in only 25% (11/44) of the HPV-positive exfoliated cells (positive predictive value, 100%; negative predictive value, 27%) with concordance in HPV types. The recurrence of the disease was significantly associated with the presence of HPV in the exfoliated cell (P= 0.01) and plasma (P= 0.007) as well as high viral load in the exfoliated cell (P= 0.0002). Kaplan-Meier disease-free estimates have also shown the significant association between HPV prevalence in plasma and recurrence of the disease (P= 0.045). Thus, it indicates that in postradiotherapy CA-CX patients, the high viral load in the exfoliated cell as well as HPV presence in the plasma samples could be used in early detection of the patients at increased risk for disease recurrence and progression.

Human papillomavirus prevalence in postradiotherapy uterine cervical carcinoma patients: correlation with recurrence of the disease

To understand the role of human papillomavirus (HPV) in recurrence of uterine cervical cancer (CA-CX) after radiotherapy, we have analyzed the HPV prevalence in the exfoliated cells of 56 patients and their corresponding plasma. HPV DNA was detected in exfoliated cells of 78% (44/56) patients (HPV-16, 68%; HPV-18, 14%; HPV-X [other than 16, 18], 11%; and mixed infection of HPV-16 and HPV-18 in three cases). HPV DNA in plasma was present in only 25% (11/44) of the HPV-positive exfoliated cells (positive predictive value, 100%; negative predictive value, 27%) with concordance in HPV types. The recurrence of the disease was significantly associated with the presence of HPV in the exfoliated cell (P = 0.01) and plasma (P = 0.007) as well as high viral load in the exfoliated cell (P = 0.0002). Kaplan–Meier disease-free estimates have also shown the significant association between HPV prevalence in plasma and recurrence of the disease (P = 0.045). Thus, it indicates that in postradiotherapy CA-CX patients, the high viral load in the exfoliated cell as well as HPV presence in the plasma samples could be used in early detection of the patients at increased risk for disease recurrence and progression.

Programmed cell death as a prognostic indicator for radiation therapy in cervical carcinoma patients: A pilot study

In clinical practice, radiation therapy often fails in cervical carcinoma stage IIIB and there is a need to develop a predictive assay for prognosis of radiation treatment outcome in cancer patient. We have attempted to evaluate the relevance of changes in Membrane Fluidity (MF) and associated apoptotic cell death in cervical cancer cells after first fractionated dose of radiation therapy to treatment outcome of stage IIIB cervical carcinoma patients. Biopsies of 15 patients with histologically proven cervix cancer were collected from the patients before and 24 h after first fractionated radiation dose of 2 grays (Gy). Cell suspension made in Dulbecco's Modified Eagle's Medium (DMEM) were used for further investigations and cell suspension of cervix cancer patient were used to measure MF by fluorescence polarization method and apoptotic index (AI) was determined by Tdt dUTP Nucleotide End Labeling (TUNEL) assay. A substantial increase in MF and AI was observed in cervical cancer cells irradiated ex vivo . A significant correlation ( P P > 0.1) was detected between changes in MF and treatment outcome of patients. Preliminary results showed significant change in MF and a marked increase in percentage apoptosis of cervix cancer cells irradiated ex vivo . The changes in AI after first fractionated dose of radiotherapy in cervical carcinoma patients may provide a predictor of prognosis for radiotherapy in uterine cervical carcinoma patients.

Prognostic significance of c-erbB-2/HER2 expression in advanced uterine cervical carcinoma with para-aortic lymph node metastasis treated with radiation therapy

This paper looks at whether c-erbB-2/HER2 expression in uterine cervical carcinoma before treatment is a predictive parameter of prognosis in patients with para-aortic lymph node metastasis (PALN) in advanced disease after treatment with radiation therapy (RT). Twenty-one patients with PALN at the first visit and/or during follow-up and treated with RT for PALN lesions were studied. Their clinical stages were IIIB or greater and they were referred to the National Institute of Radiological Sciences Hospital for RT between 1987 and 1995. They consisted of 12 patients with PALN detected at the first visit and nine with PALN detected during the follow-up period. All patients had no distant metastasis except PALN. They were treated with a combination of external whole pelvis and intracavitary irradiation to the primary pelvic lesions. The PALN was treated with external irradiation alone with anterior-posterior parallel opposed fields and anterior oblique fields or anterior-posterior parallel opposed oblique fields. The average total dose to PALN was 53.3 Gy (40–61Gy). Tissue samples were obtained from cervical tumors (primary lesions) before RT. Immunohistochemical staining was performed using anti-c-erbB-2/HER2 monoclonal antibody for conventional paraffin sections. c-erbB-2/HER2 positive staining was observed in cancer membrane and cytoplasm. Nine specimens were positive for c-erb-B2/HER2 and the total positive rate was 43%. The 5-year survival rate was 38% for all patients. The 5-year survival rate of the c-erbB-2/HER2 positive patients was 28%, representing a trend toward poorer prognosis than the 52% of negative patients (P=0.10). Multivariate analysis using Cox proportional hazards model showed that c-erbB-2/HER2 was an independent prognostic factor (P= 0.024). The present study suggests that c-erbB-2/HER2 expression of cervical tumors might be a predictive parameter of prognosis after radiation therapy for PALN of very advanced uterine cervical carcinoma patients.

Concurrent Chemoradiotherapy in Locally Advanced Carcinoma of the Uterine Cervix Preliminary Results of Phases III Prospective Randomized Trial.

A prospective, randomized phase III, clinical trial was performed to assess treatment related acute toxicity, early response and survival difference, between a monthly 5-FU cisplatin, and a weekly cisplatin group alone, for concurrent chemoradiotherapy in the locally advanced uterine cervical carcinoma patients. MATERIALS AND METGODS: Between March 1998 and March 2000, 35 patients, with locally advanced (FIGO stage IIB to IVA) cervical carcinoma, were studied, but 5 patients were excluded inform the analysis due to their refusal of treatment. The patients were randomly assigned to 'monthly 5-FU cisplatin' (arm I), or 'weekly cisplatin' (arm II), groups. The patients of arm I received 5-FU cisplatin (5-FU 1,000 mg/m2/day cisplatin 20 mg/m2/day, IV continuous infusion, for 5 days, 3 cycles with 4-week intervals) with radiation therapy. Those of arm II received only cisplatin (cisplatin 30 mg/m2/day, IV bolus, 6 cycles with 1-week intervals) with radiation therapy. The radiation therapy consisted of external beam irradiation of 41.4~50.4 Gy/23~28 fractions, and high dose rate intracavitary treatments, delivering a dose of 30~35 Gy to point A in 6~7 fractions. During intracavitary radiation, a parametrial boost was delivered for a point B dose of 60 Gy in the non-thickened side, and 65 Gy in the thickened side. Treatment related acute toxicities were assessed using Radiation Therapy Oncology Group (RTOG) acute morbidity scoring criteria. The response to treatment, and survival, were analyzed. The median follow-up period was 19 months. The FIGO stage distributions of arm I (n=16) and arm II (n=14) were as follows; IIB 10, IIIA 1, IIIB 4, IVA 1 in arm I, 12, 0, 1 and 1 in arm II respectively. The compliance of both arms were 80.0% and 93.3%, respectively (p=0.37). During radiation therapy, the incidences of leukopenia, greater than RTOG grade 2, were 25.0%, 14.3%, respectively. There were no patients with gastrointestinal or genitourinary toxicity greater than RTOG grade 2. The complete response rates at 3 months, following radiation therapy, were 87.5% and 92.9% respectively. Two-year disease free survival rates were 81.3%, 85.7%, respectively, for each arms. There was no significant difference in response to treatment, or patterns of failure, between the monthly FP and weekly cisplatin arms. Although there were no statistically significant differences, the patients of the weekly cisplatin arm had better compliance. More patients, and a longer follow up, are needed for improved evaluation of the regimen.

Sensory and motor dysfunction assessed by anorectal manometry in uterine cervical carcinoma patients with radiation-induced late rectal complication

Purpose: To investigate the effects of radiation on anorectal function in patients with carcinoma of the uterine cervix. Methods and Materials: Anorectal manometry was carried out on 24 patients (complication group) with late radiation proctitis. All of the manometric data from these patients were compared with those from 24 age-matched female volunteers (control group), in whom radiation treatment had not yet been performed. Results: Regardless of the severity of proctitis symptoms, 25% of patients demonstrated all their manometric data within the normal range, but 75% of patients exhibited one or more abnormal manometric parameters for sensory or motor functions. Six patients (25%) had an isolated sensory dysfunction, eight patients (33.3%) had an isolated motor dysfunction, and four patients (16.7%) had combined disturbances of both sensory and motor functions. The maximum tolerable volume, the minimal threshold volume, and the urgent volume in the complication group were significantly reduced compared with those in the control group. The mean squeeze pressure in the complication group was significantly reduced, whereas the mean resting pressure and anal sphincter length were unchanged. Conclusions: Physiologic changes of the anorectum in patients with late radiation proctitis seem to be caused by a variety of sensory and/or motor dysfunctions in which many different mechanisms are working together. The reduced rectal reservoir capacity and impaired sensory functions were crucial factors for functional disorder in such patients. In addition, radiation damage to the external anal sphincter muscle was considered to be an important cause of motor dysfunction.

A novel tumor-associated antigen expressed in human uterine and ovarian carcinomas

A large number of monoclonal antibodies (MoAbs) against human tumor cells have been generated and it has been shown that these MoAbs are useful tools in the diagnosis and treatment of cancer patients, as well as in the basic investigation of the oncogenesis and characterization of cancer cells. The 22-1-1 MoAb was established by cell fusion between mouse myeloma cells and spleen cells derived from mice immunized with the human uterine cervical adenocarcinoma cell line, SiSo. The tissue distribution and biologic characteristics of the 22-1-1 antigen (Ag) were examined. The 22-1-1 Ag was distinct from the known tumor-associated antigens such as YH 206, GA 733, CA 125, carcinoembryonic antigen, and sialyl Le(x) molecules in an expression pattern in human tumor cell lines. An immunohistochemical study revealed that 22-1-1 Ag was expressed in 87.5% of uterine cervical adenocarcinomas, 66% of uterine endometrial adenocarcinomas, and 58.8% of ovarian carcinomas. Moreover, 22-1-1 Ag was detected in 87.7% of uterine cervical squamous cell carcinomas; however, it was not detected in 87.7% of uterine cervical or ovarian tissues, except in uterine endometrial glands, in which its expression was observed at low levels. The 22-1-1 Ag was secreted into cell culture supernatant fluids and was also detected in the vaginal discharges of uterine cervical carcinoma patients. The antigenic epitope of 22-1-1 Ag was shown to be a protein with a molecular weight of 78 kilodaltons using sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. The 22-1-1 MoAb reactive to a novel tumor-associated antigen was generated. This Ag was expressed in cancer cells derived mainly from the uterus and ovary. Moreover, 22-1-1 Ag was associated in the vaginal discharges of uterine cervical carcinoma patients. 22-1-1 MoAb is a potential tool for the study of oncogenesis and the management of cancer patients.