Plasma cholinesterase activity in patients with uterine cervical cancer during radiotherapy

The objectives of this study were to investigate: 1) the activity of pseudocholinesterase (PChE) in patients with uterine cervical cancer in different stages (uterine cervical carcinoma in stages II b and III and recurrent cervical carcinoma in stages III and IV a,b) and to compare it to the enzyme activity in patients with benign tumour of the uterus, and 2) the effects of radiotherapy on enzyme activity in those patients with uterine cervical carcinoma for which the chosen treatment was radical radiotherapy. Thirty patients with uterine cervical carcinoma in stages II b and III (Group A), sixteen patients with recurrent cervical carcinoma in stages III and IV a,b (Group B) and thirty-eight patients with benign tumours of the uterus (control, Group C) were evaluated and their PChE activity was determined prior to any treatment (pre-therapy enzyme activity). All eighty-four patients were free of any liver disease. The results have shown that the patients of Group A had the pre-therapy PChE activity practically identical to those in group C, but patients of Group B had significantly lower values of PChE with respect to enzyme activities of Groups A and C (p < 0.001). That is to say, PChE activity was influenced by the extent to which the malignancy had spread. Radical radiotherapy (up to 8 weeks in doses higher than 50 Gy into point A; average 80 Gy) which was the chosen treatment only for patients from group A did not cause a significant inhibition of PChE activity in any patients in comparison with their control values. With regard to the role of PChE in hydrolysis of succinylcholine, our results about the influence of the malignant disease and the radiotherapy on PChE activity are clinically significant.     

The effect of brachytherapy on antioxidant status and lipid peroxidation in patients with cancer of the uterine cervix

The aim of this study was to investigate the effect of brachytherapy on lipid peroxidation and antioxidant status in patients with uterine cervix cancer. The study was conducted on 84 uterine cervix cancer patients from the Brachytherapy Department of the Regional Centre of Oncology in Bydgoszcz. Patients with uterine cervix cancer were found to have elevated levels of lipid peroxidation and antioxidant defence system impairment relative to healthy females. The results of the study indicate that brachytherapy has no direct effect on the antioxidant system of patients with uterine cervical carcinoma. However, the normalisation of catalase and glutathione peroxidase activity and erythrocyte TBARS level observed six months after the end of therapy may be due to the arrest of the progression of the disease.     

Germline mutation in RNASEL predicts increased risk of head and neck, uterine cervix and breast cancer

THE BACKGROUND: Ribonuclease L (RNASEL), encoding the 2'-5'-oligoadenylate (2-5A)-dependent RNase L, is a key enzyme in the interferon induced antiviral and anti-proliferate pathway. Mutations in RNASEL segregate with the disease in prostate cancer families and specific genotypes are associated with an increased risk of prostate cancer. Infection by human papillomavirus (HPV) is the major risk factor for uterine cervix cancer and for a subset of head and neck squamous cell carcinomas (HNSCC). HPV, Epstein Barr virus (EBV) and sequences from mouse mammary tumor virus (MMTV) have been detected in breast tumors, and the presence of integrated SV40 T/t antigen in breast carcinomas correlates with an aggressive phenotype and poor prognosis. A genetic predisposition could explain why some viral infections persist and induce cancer, while others disappear spontaneously. This points at RNASEL as a strong susceptibility gene. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the implication of an abnormal activity of RNase L in the onset and development of viral induced cancers, the study was initiated by searching for germline mutations in patients diagnosed with uterine cervix cancer. The rationale behind is that close to 100% of the cervix cancer patients have a persistent HPV infection, and if a defective RNase L were responsible for the lack of ability to clear the HPV infection, we would expect to find a wide spectrum of mutations in these patients, leading to a decreased RNase L activity. The HPV genotype was established in tumor DNA from 42 patients diagnosed with carcinoma of the uterine cervix and somatic tissue from these patients was analyzed for mutations by direct sequencing of all coding and regulatory regions of RNASEL. Fifteen mutations, including still uncharacterized, were identified. The genotype frequencies of selected single nucleotide polymorphisms (SNPs) established in the cervix cancer patients were compared between 382 patients with head and neck squamous cell carcinomas (HNSCC), 199 patients with primary unilateral breast cancer and 502 healthy Danish control individuals. We found that the genotype frequencies of only one of the 15 mutations, the yet uncharacterized 5'UTR mutation rs3738579 differed significantly between cancer patients and control individuals (P-value: 4.43x10(-5)). CONCLUSION/SIGNIFICANCE: In conclusion, we have discovered an increased risk, a heterozygous advantage and thereby a protective effect linked to the RNASEL SNP rs3738579. This effect is found for patients diagnosed with carcinoma of the uterine cervix, HNSCC, and breast cancer thus pointing at RNASEL as a general marker for cancer risk and not restricted to familial prostate cancer.     

A rapid prognostic electrophoretic assay for serum lipid conjugates in carcinoma uterine cervix and breast

The levels of cholesterol and lipid associated sialic acid in sera of patients with carcinoma uterine cervix and breast cancer were determined using agarose electrophoresis and precipitation method. Elevated level of lipid associated sialic acid was found, that was specifically reflected only in LDL and VLDL fractions. In carcinoma uterine cervix patients, cholesterol in low density lipoprotein increased with corresponding decrease in high density lipoprotein and there was no change in total as well as VLDL cholesterol content. But breast cancer patients were found to have higher concentrations of both total and high density lipoprotein cholesterol. A good positive correlation was found between electrophoresis and precipitation methods for the lipoprotein analysis. We recommend electrophoretic method for rapid routine analysis.     

HLA types in women with cervical human papillomavirus (HPV) lesions prospectively followed up for 10 years

Certain genotypes of HPV have been recently implicated in the etiology of carcinoma of the uterine cervix. In order to determine whether HLA antigen‐controlled immunoregulatory functions have a role in the pathogenesis of HPV infections, class I and II HLA antigen typing was carried out on a series of 96 randomly selected women who were part of a cohort of 530 women prospectively followed up for cervical HPV infections in our clinic since 1981. The frequency of the DQ3 antigen, which has previously been reported to be increased among cervical cancer patients, was decreased in our HPV patients compared with the control group of Finnish women, but it was slightly increased in HPV16‐infected women ( P =0.0812). However, we were able to demonstrate that HLA‐DR5 antigen is significantly increased (i) in patients with high grade cervical intraepithelial neoplasia (CIN) ( P <0.02), and (ii) in women harbouring the high risk HPV type 16 ( P =0.0003), thus confirming earlier reports of an association of this HLA antigen and cervical cancer. Such a close association between the high risk HPV type 16 with an HLA antigen might have important implications in the possible immunogenetic basis of the increased risk for squamous cell carcinoma of the uterine cervix.     

Akt and XIAP regulate the sensitivity of human uterine cancer cells to cisplatin,doxorubicin and taxol

We have investigated the interrelationship between two anti-apoptotic factors, XIAP and Akt, and their role in chemoresistance of uterine cancer cells. We used one cervical cancer cell line (HeLa) and two endometrial cancer cell lines (KLE and Ishikawa) as a model. The three drugs decreased Akt and XIAP content and induced apoptosis in P-Akt-negative HeLa cells. In P-Akt1/3-positive Ishikawa cells apoptosis induction correlated with XIAP decrease. P-Akt1/2/3-positive KLE cells showed maximum chemoresistance as XIAP and Akt levels/phosphorylation remained stable in response to the three drugs, and only cisplatin could significantly induce apoptosis. We found that XIAP and Akt were functionally linked in uterine cancer cells, as downregulation of XIAP with RNAi decreased P-Akt levels, and inhibition of PI3-K/Akt activity using LY294002 decreased XIAP content. Overexpression of constitutively active Akt isoforms in HeLa cells induced isoform-specific sensitivity to doxorubicin and taxol but not cisplatin. XIAP RNAi increased the cell-specific sensitivity to cisplatin and doxorubicin but not taxol. Finally, we found P-Akt immunoreactivity in epithelial cells from multiple human endometrial carcinoma tumors, suggesting that Akt may also regulate chemosensitivity in uterine cancers in vivo. Altogether these results highlight an intertwined role for specific Akt isoforms and XIAP in chemoresistance of uterine cancer cells.     

Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy

The major hurdle for cancer vaccines to be effective is posed by tumor immune evasion. Several common immune mechanisms and mediators are exploited by tumors to avoid immune destruction. In an attempt to shed more light on the immunosuppressive environment in uterine tumors, we analyzed the presence of PD-L1, PD-L2, B7-H4, indoleamine 2,3-dioxygenase (IDO), galectin-1, galectin-3, arginase-1 activity and myeloid-derived suppressor cell (MDSC) infiltration. IDO, PD-L1, PD-L2 and B7-H4 were analyzed by immunohistochemistry. PD-L2 was mostly expressed at low levels in these tumors. We found high IDO expression in 21 % of endometrial carcinoma samples and in 14 % of uterine sarcoma samples. For PD-L1 and B7-H4, we found high expression in 92 and 90 % of endometrial cancers, respectively, and in 100 and 92 % of the sarcomas. Galectin-1 and 3 were analyzed in tissue lysates by ELISA, but we did not find an increase in both molecules in tumor lysates compared with benign tissues. We detected expression of galectin-3 by fibroblasts, immune cells and tumor cells in single-cell tumor suspensions. In addition, we noted a highly significant increase in arginase-1 activity in endometrial carcinomas compared with normal endometria, which was not the case for uterine sarcomas. Finally, we could demonstrate MDSC infiltration in fresh tumor suspensions from uterine tumors. These results indicate that the PD-1/PD-L1 interaction and B7-H4 could be possible targets for immune intervention in uterine cancer patients as well as mediation of MDSC function. These observations are another step toward the implementation of inhibitors of immunosuppression in the treatment of uterine cancer patients.     

Extracellular matrix components and proteolytic enzymes in uterine cervical carcinoma

The important components of mucopolysaccharides and collagen have been analyzed in tissues of control and carcinoma of uterine cervix. Among these components hyaluronic acid and chondroitin sulphate levels were found to be increased, whereas decreased level of collagen was observed in uterine cervical carcinoma. Serum cathepsin B, D and acid and alkaline phosphatases have also been analyzed in controls and carcinoma patients before and after treatments. The activities of these enzymes have been found to increase prominently in advanced stages. Among these enzymes cathepsin B and alkaline phosphatase have exhibited remarkable increase in activity in uterine cervical carcinoma. Different modes of treatment exerted reversion of the elevated activities of these enzymes. However, combined therapy type II (radiation combined with cisplatin and cyclophosphomide) seems to be more effective in reverting the activities of these enzymes to normal levels.     

MANAGEMENT OF CARCINOMA OF THE UTERINE CERVIX

The long, occult phase of pre-invasive carcinoma of the uterine cervix provides the clinician with his greatest opportunity in the actual prophylaxis of invasive cancer. By the use of four-quadrant biopsies and Papanicolaou smears, the authors increased by almost 20 times the frequency of diagnosis of preinvasive carcinoma of the uterine cervix.Radiation therapy of invasive carcinoma in 147 patients produced five-year “cure” in 84 per cent of stage I cases, 65 per cent of stage II cases. The over-all rate for stages I to IV, inclusive, was 51 per cent.Surgical management of this form of cancer, with preservation of the urinary tract, is an inadequate operation as judged by the extirpative standards observed in operations for cancer at other major anatomical sites.Improvements in technique of irradiation, more accurate measurements of depth dosage at critical sites, and more uniform dosage throughout the parametrial areas, have decreased the incidence of major complications of irradiation.Radical panhysterectomy and pelvic node dissection should be reserved for patients proved to have radioresistant lesions.The application of routine block dissection of pelvic nodes for Stage I and Stage II lesions, clinically controlled by irradiation, is of doubtful theoretic, and no evident practical value.Subject to future evaluation, pelvic eviscerative procedures seem to offer some salvage in cases of recurrent (occasionally primary) advanced lesions in rigidly selected patients.     

Establishment and characterization of a human cell line derived from a uterine papillary serous carcinoma with wild-type p53 function

Uterine papillary serous carcinoma is an uncommon histologic subtype of endometrial cancer that behaves aggressively and has a poor prognosis. We successfully established a uterine papillary serous carcinoma cell line. The population-doubling time was approximately 16 h. Although loss of p53 function is considered critical for the molecular pathogenesis of uterine papillary serous carcinoma, p53 was not only mutated but functionally active in this cell line. This newly established cell line should be useful for investigating the characteristics of uterine papillary serous carcinoma.     

Effect of radiotherapy and chemoradiotherapy on circulating antioxidant system of human uterine cervical carcinoma

Circulating lipid peroxide, antioxidant components and the activities of defense enzymes were estimated in uterine cervical carcinoma patients (before and after radiotherapy and radiotherapy combined chemotherapy) and compared with controls. Some of the antioxidant components such as glutathione, vitamin E and selenium are reduced in cervical cancer. The reduced levels of vitamin E and glutathione were normalized after treatment. Erythrocyte lipid peroxide (E-LPx) and erythrocyte membrane lipid peroxide (EM-LPx) levels were found to be increased in all the stages of uterine cervical carcinoma. The important antioxidant enzymes such as erythrocyte superoxide dismutase (E-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST) and glucose-6-phosphate dehydrogenase (G6PDH) were found to be decreased in uterine cervical carcinoma. These altered biochemical parameters were reversed to normal, of course with varied degree after different mode of therapy. Significant normalization was observed in Type 11 chemoradiotherapy.     

Transient form of serum albumin in gynecologic cancer

The frequency of diagnostic errors in examination of 3827 patients with gynecological cancer diseases accounted for 21.6 up to 35%. The conformation of serum albumin in these patients was studied by means of different biochemical assays. The determination of the amount of the transitory form of albumin by reprecipitation with trichloroacetic acid appeared the most valuable for practical uses. Structural injuries to albumin depended on the localization, pattern and stage of the disease, and features of tumor metastatic spreading. The amount of the transitory form in patients with benign tumors and tumor-like processes in the ovaries (4.5-23.5%), hydatidiform mole (25%), uterine myoma (2-12.6%) rose insignificantly (5 +/- 2% in control) and increased in patients with initial stages of malignant tumors of the ovaries and uterus (28.9-43.7%). In uterine cervix carcinoma and uterine body sarcoma (stage II and higher stages) as well as in ovarian carcinoma, stages III and IV, its amount reached 57-100%.     

Glutathione level and its relation to radiation therapy in patients with cancer of uterine cervix

Glutathione functions as an important antioxidant in the destruction of hydrogen peroxide and lipid peroxides by providing substrate for the glutathione peroxidase and also promotes the ascorbic acid. Glutathione plays a vital role in detoxification of xenobiotics, carcinogens, free radicals and maintenance of immune functions. The study was aimed to determine plasma glutathione as well as erythrocyte glutathione and glutathione peroxidase in patients with invasive cervical carcinoma (n = 30) before initiation and after completion of radiotherapy and subsequently, at the time of first three monthly follow-up visit. The levels of plasma glutathione, erythrocyte glutathione and glutathione peroxidase activity were found to be lower in all cervical cancer patients as compared to age matched normal control women. The study indicates a change in antioxidant status in relation with the glutathione system among patients with invasive carcinoma of the uterine cervix. This study also demonstrates the effect of radiation therapy on this antioxidant system.     

The role of mast cell tryptase in neoangiogenesis of premalignant and malignant lesions of the uterine cervix.

Recently, mast cell tryptase has been identified as another potent proangiogenic factor in tumors, along with fibroblast and vascular endothelial growth factors. Its role has been studied in a number of cancers, including carcinoma of the uterine cervix, with discordant results. Our aim was to study the expression of tryptase and bFGF in mast cells (MCs) during development of neoangiogenesis in premalignant and malignant lesions of the cervix. Biopsy specimens from 21 patients without cancer and from 63 patients with dysplasias and squamous cell carcinomas were used. They were stained with Alcian blue-safranin O (ABSO) and immunostained with specific antibodies against factor VIII, CD105, tryptase, and bFGF. Tryptase-positive mast cells increased with tumor progression and were close to newly formed blood vessels. Vascularization showed a linear increase from dysplasia to invasive cancer. We suggest that MC tryptase may upregulate neoangiogenesis in carcinogenesis of the uterine cervix.     

Nationwide Surveillance in Uterine Cancer: Survival Analysis and the Importance of Birth Cohort: 30-Year Population-Based Registry in Taiwan

Introduction

Uterine cancer was the most rapidly increasing malignancy and the second most common gynecologic malignancy in Taiwan.

Methods

We analyzed the secular trend of uterine cancer incidence and compare the survival of women with uterine carcinomas and uterine sarcomas in Taiwan. Data on women diagnosed with uterine cancer between 1979 and 2008 were obtained from the Taiwan cancer registry. Survival data were analyzed by using Kaplan-Meier and Cox proportional hazards regression methods.

Results

Records of 11,558 women with uterine carcinomas and 1,226 women with uterine sarcomas were analyzed. The age-adjusted incidence rate of endometrioid adenocarcinoma increased from 0.83 per 100,000 women per year between 1979 and 1983 to 7.50 per 100,000 women per year between 2004 and 2008. The 5-year survival rate of women with endometrioid adenocarcinoma (83.2%) was higher than that for women with clear cell carcinoma (58.3%), serous carcinoma (54.4%), and carcinosarcoma (35.2%) (p<0.0001, log-rank test). The 5-year survival rates of women with low grade endometrial stromal sarcoma, endometrial stromal sarcoma, leiomyosarcoma (LMS), and adenosarcoma were 97.5%, 73.5%, 60.1%, and 77.2%, respectively (p<0.0001, log rank test). The histologic type of endometrioid adenocarcinoma, young age, and treatment period after 2000 were independent, favorable prognostic factors in women with uterine carcinomas by multivariate analysis. The histologic type of LMS, old age, and treatment period after 2000 were independent, poor prognostic factors in women with uterine sarcomas by multivariate analysis.

Conclusions

An increase over time in the number of patients with endometrioid adenocarcinomas was noted in this 30-year, nationwide, population-based study. Histologic type, age and treatment period were survival factors for uterine cancers. A more comprehensive assessment of uterine cancers and patient care should be undertaken on this increasingly common type of cancer.     

Carcinoma of the Lower Uterine Segment (LUS): Clinicopathological Characteristics and Association with Lynch Syndrome

Endometrial cancer arises from the uterine body and fundus in many cases, but can also originate from the lower region of the uterine body through the upper region of the cervix. Such tumors are referred to as carcinoma of the lower uterine segment (LUS) or isthmus, and account for 3-6.3% of all cases of endometrial cancer. This relatively low incidence has permitted performance of only small-scale studies, but the clinical and pathological characteristics of carcinoma of the LUS in all these reports have differed from those of other endometrial cancers. Generally, endometrial cancer is classified into estrogen-dependent endometrioid adenocarcinoma (designated as type I), and non-endometrioid types that are less associated with estrogen and include poorly differentiated adenocarcinoma (type II). In some reports, carcinoma of the LUS has been found to have type II characteristics. Carcinoma of the LUS has also been associated with Lynch syndrome, a hereditary disease with frequent development of colorectal, endometrial, and ovarian cancers. Lynch syndrome is thought to be induced by mismatch repair gene mutation. The frequency of Lynch syndrome in cases of general endometrial cancer is 1-2%. In contrast, the frequency in patients with carcinoma of the LUS is much higher, with up to 29% of cases diagnosable with Lynch syndrome and a high frequency of hMSH2 mutation found in one study. This suggests that further investigation of the clinical and pathological characteristics of carcinoma of the LUS and the association with Lynch syndrome is required through performance of a large-scale survey.     

Small cell carcinoma of the uterine cervix--an uncommon variant of cervical cancer with neuroendocrine features

Small cell carcinoma (SCC) of the uterine cervix represents an uncommon variant of cervical cancer with an extremely aggressive biologic behavior, minimum survival chances and rapid and fatal clinical course. This retrospective study included 73 cases of patients treated for invasive squamous carcinoma of the uterine cervix at stages Ib and IIa at the Department of Gynecology in the years 1996-2000. Six patients (8%) with SCC were identified among all cases, sharing the clinical features of young age and early failure of appropriate radical treatment in the presence of apparently low stage disease. Neuroendocrine cellular characteristics were assessed by the biotin-streptavidin-peroxidase (LSAB) method using antibodies against neuron-specific enolase (NSE; DAKO), chromogranin A (CGA; DAKO) and synaptophysin (SYN; DAKO). All tumors examined were positive for NSE and/or CGA and/or SYN. Although the presence of neuroendocrine features appears to correlate with decreased survival, the number of patients is not large enough to determine statistical significance. However, the results confirm that SCC of the uterine cervix is one of the most aggressive tumors of the female genital tract.     

Elevation of liver-galactosylhydroxylysyl glucosyltransferase activity in human primary hepatocellular carcinoma

The activity of L-GGT (EC 2.4.1.66), an enzyme catalyzing the intracellular biosynthesis of collagen, was determined in human primary hepatic cancer, acute viral hepatitis and cirrhotic liver tissues and compared to the mean level of enzyme activity in normal human liver tissues. The mean levels of L-GGT activity in primary hepatocellular carcinoma (PHC), acute viral hepatitis and cirrhotic tissues were 7.78, 2.69 and 2.16 times the mean level of enzyme activity in normal human liver tissues. The mean level of L-GGT activity in PHC was 3.61 times the mean level of L-GGT activity in cirrhosis and 2.90 times the mean value of liver enzyme activity in acute viral hepatitis. The findings in this study provide a basis for the highly elevated serum values of this intracellular enzyme in patients with primary hepatic cancer and the data indicate that L-GGT activity may be increased in primary liver cancer to compensate for an increased rate of collagen synthesis.