HPV infection and number of lifetime sexual partners are strong predictors for ‘natural’ regression of CIN 2 and 3

The aim of this paper was to evaluate the factors that predict regression of untreated CIN 2 and 3. A total of 93 patients with colposcopic persistent CIN 2 and 3 lesions after biopsy were followed for 6 months. Human papillomavirus (HPV) types were determined by polymerase chain reaction at enrolment. We analysed the biologic and demographic predictors of natural regression using univariate and multivariate methods. The overall regression rate was 52% (48 out of 93), including 58% (22 out of 38) of CIN 2 and 47% (26 out of 55) of CIN 3 lesions (P=0.31 for difference). Human papillomavirus was detected in 84% (78 out of 93) of patients. In univariate analysis, 80% (12 out of 15) of lesions without HPV regressed compared to 46% (36 out of 78) of lesions with HPV infection (P=0.016). Women without HPV and those who had a resolution of HPV had a four-fold higher chance of regression than those with persistent HPV (relative odds=3.5, 95% CI=1.4-8.6). Women with five or fewer lifetime sexual partners had higher rates of regression than women with more than five partners (P=0.003). In multivariate analysis, HPV status and number of sexual partners remained as significant independent predictors of regression. In conclusion, HPV status and number of lifetime sexual partners were strongly predictive of regression of untreated CIN 2 and 3

The Wnt-dependent signaling pathways as target in oncology drug discovery

Our current understanding of the Wnt-dependent signaling pathways is mainly based on studies performed in a number of model organisms including, Xenopus, Drosophila melanogaster, Caenorhabditis elegans and mammals. These studies clearly indicate that the Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Wnt pathways have been shown to regulate cell proliferation, morphology, motility as well as cell fate. The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several pathological disorders including cancer, retinopathy, tetra-amelia and bone and cartilage disease such as arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer’s disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research. In this review, we wish to present a focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development. We also want to provide information on a selection of potential drug targets within these pathways for oncology drug discovery, and summarize current data on approaches, including the development of small-molecule inhibitors, that have shown relevant effects on the Wnt-dependent signaling pathways

DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity

β-carotene treatment of cervical intraepithelial neoplasia: A phase II study

The use of Papanicolaou smears for cervical cancer screening has led to an increased detection of preinvasive conditions of the cervix, cervical intraepithelial neoplasia (CIN). Epidemiological studies have shown an association between low levels of dietary β-carotene and CIN. In this Phase II study, we have explored the effect of p.o. β-carotene administration on CIN I and II. Patients with documented CIN I or II were treated with 30 mg daily of β-carotene for 6 months. Response rates were determined at 0, 3, 6, and 12 months with cytology, colposcopy, and/or biopsies. Levels of β- carotene and vitamin E were determined at the same time intervals in vaginal mucosa cells and serum. Response rates were 18 of 30 (60%), 21 of 30 (70%), and 10 of 30 (33%) at 3, 6, and 12 months, respectively. Significant changes occurred in the serum β-carotene levels over time. Median levels over 2200 mg/ml were found at 3 and 6 months versus a baseline median level of 111 (P < 0.0001). Significant increases were also noted in the β-carotene levels of the vaginal mucosa compared to baseline (P = 0.01) and a significant correlation was noted between serum and vaginal β-carotene levels as well (P < 0.0001). This study indicates that a large percentage of patients with CIN I and II will respond clinically to p.o. β-carotene supplementation. There is a positive relationship between serum and tissue levels of β-carotene which suggests that serum levels can be used for monitoring purposes. Because of these encouraging results, prospective randomized studies are ongoing comparing the efficacy of β-carotene against an untreated control arm

A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711). Southwest Oncology Group.

PurposeThe results of Southwest Oncology Group Study 8711 (Group 2B) are presented. The objective was to evaluate the natural history of sperm concentration and selected hormonal parameters in patients with testicular cancer treated with orchiectomy and radiotherapy.Methods and materialsOf a total of 207 patients enrolled on SWOG 8711, 53 pure seminoma patients were identified who were treated with orchiectomy and radiotherapy only. Sperm concentration, follicle-stimulating hormone (FSH) levels, and sexual satisfaction scores were the main parameters followed.ResultsA fraction of the patients were infertile prior to receiving radiotherapy. Our analysis indicates that incidental radiation dose to the remaining testicle affects time to recovery of fertility, and at an aggregate level, changes in FSH mirror changes in sperm concentration over time. This phenomenon is the same as that described in patients free from testicular cancer. These men evaluated their sexual activity as good after orchidectomy.ConclusionOur data support the use of clamshell-type testicular shields as a means of providing maximum protection to the remaining testicle

A micromethod for determination of terminal deoxynucleotidyl transferase (TdT) in the diagnostic evaluation of acute leukemias

A micromethod for the determination of TdT in peripheral leukocytes and bone marrow cells has been developed that allows unequivocal identification and quantitation of TdT in less than 1 X 10(6) leukocytes from ALL patients, i.e., in 1 ml of peripheral blood and/or 0.5 ml of bone marrow obtained during routine clinical sampling. The method involves disruption of cell pellet with high salt and detergent followed by centrifugation of extracts at 12,000 X g and partial purification on phosphocellulose matrix by a batch elution technique using a standard laboratory microcentrifuge. Using this microassay, TdT activities have been determined in 500 samples of peripheral blood and bone marrow of 240 adult patients with acute leukemias (86 ALL, 108 ANLL, 44 blastic CML, two acute leukemias following P. vera). From an analysis of our data based on TdT activity, cell surface markers and growth patterns in soft agar and observations published in the literature, it can be concluded that the frequencies of TdT + phenotypes in the various clinical-morphological diagnostic groups are approximately 95% in ALL, 10% in ANLL, 50% in AUL, and 35% in blastic CML. Since the presence of high TdT activity is clearly associated with clinical response to specific forms of chemotherapy in blastic CML and most probably, also in ANLL, the determination of TdT should be considered in all cases of acute leukemias to objectively define prognostically important subgroups which can not be diagnosed by conventional means