Screening program in ovarian cancer: A logical step in clinical management? A meta-analysis

ObjectiveTreatment of ovarian cancer (OC) is a challenge and its poor prognosis still remains a problem of major importance. Due to the lack of early and specific symptoms, the vast majority of women are diagnosed with an advanced stage disease. The aim of this meta-analysis is to evaluate the impact of OC screening program in asymptomatic women on clinical outcomes.Methods and materialA systematic literature electronic search was conducted in Pubmed, Medline, Scopus, and ClinicalTrials.gov databases. Articles were selected with a systematic approach. Clinical trials concerning screening strategy compared with usual care in asymptomatic OC women were considered, without any restrictions on the publication date. Trials were eligible if participants were asymptomatic and postmenopausal women. Outcomes included OC diagnosis and disease specific mortality. The pooled relative risk (RR) was calculated using a fixed-effects model.ResultsOverall, 3 randomized controlled trials met inclusion criteria, totaling 353,590 asymptomatic women. In total 177,188 women were assigned to screening program, and 176,402 women were assigned to usual care. The risk of OC diagnosis, both overall and at an early stage, was higher in screening group (RR = 1.07, 95% CI: 0.98-1.18; and RR = 1.30, 95% CI: 1.14-1.49, respectively). The RR for disease specific mortality was 0.96 (95% CI: 0.85-1.10).ConclusionOur results suggest the possible benefit of OC screening program in term of early stage diagnosis and reduced specific OC mortality. Further studies of environmental or constitutional factors may lead to the identification of patient populations that could benefit from a screening program.     

Chemotherapy resistant ovarian cancer in carriers of an hMSH2 mutation?

Hereditary Non-Polyposis Colorectal Cancer (HNPCC, Lynch syndrome) is an autosomal dominant condition of cancer susceptibility with high penetrance, characterised by early onset of colon tumours as well as a variety of extracolonic tumours including ovarian cancer and, in particular, cancer of the endometrium. Germline mutations in one of five DNA-mismatch repair (MMR) genes (hMLH1, hMSH2, hMSH6, PMS1, PMS2) are known to cause HNPCC. To date, mutations in two of these genes (hMSH2 and hMLH1) are found in the majority of mutation positive families. Recent literature suggests that especially hMSH2 mutations are associated with extracolonic tumours. We describe two women from an HNPCC family carrying an hMSH2 mutation (deletion of exon 6 of this gene) who developed ovarian cancer. In these patients (full cousins) the ovarian cancers were noted for their aggressive development and rapid recurrence after surgical debulking and during regular multichemotherapy including Cisplatin. This report strengthens recent in vitro studies suggesting an involvement of MMR-gene mutations in ovarian cancer cell biology with decreased susceptibility to Cisplatin therapy. The possible implications for the therapy of ovarian cancer, the screening and genetic counselling of family members are discussed.     

Dietary retinol: prevention or promotion of carcinogenesis in humans?

A number of epidemiologic studies have found that vitamin A is associated with a reduced risk for human cancers. Dietary vitamin A indices reflect intake of several compounds in the diet including retinol and provitamin A carotenoids such as -carotene, and recent cancer epidemiology studies have attempted to distinguish effects of retinol from those of -carotene. While -carotene has been associated consistently with a reduced risk for a number of human cancers, particularly epithelial cancers, retinol is generally found to be unassociated with, or positively associated with, risk for many cancers. An apparent enhancement of carcinogenesis has been observed in numerous studies, particularly of cancer of the esophagus, oral cavity, pharynx, larynx, stomach, colon, and rectum. While this finding could be artifactual, experimental studies in animals as well as mechanistic considerations suggest that this effect deserves serious consideration. As discussed in this article, an apparent enhancement of carcinogenesis could be related to an ethanol/retinol interaction, and/or a mechanism involving pro-oxidant activity of retinol but anti-oxidant activity of -carotene. This article concludes with suggestions for further research to help clarify the association between retinol and human carcinogenesis.Des Mayne and Zheng are in the Department of Epidemiology and Public Healtb, Yale University School of Medicine. Dr Grabam is in the Department of Social and Preventive Medicine, State University of New York at Buffalo, Buffalo, NY, USA. Address correspondence to Dr Mayne at the Department of Epidemiology and Public Health, Yale University School of Medicine, P.O. Box 3333, New Haven, CT 06510, USA. The research was supported by NIH grant CA-42101.     

Aneuploidy of chromosome Y in prostate tumors and seminal vesicles: A possible sign of aging rather than an indicator of carcinogenesis?

Chromosome Y aneuploidies have been reported as one of the recurrent cytogenetic findings in prostate cancer (PCa) and many other solid and hematological tumors. We have studied this aneuploidy in 28 patients with PCa undergoing radical prostatectomy, one patient with benign hyperplasia (BPH) and four organ donors. A total of 72 samples have been studied: 17 tumors, 25 nontumor prostate tissues, 1 BPH, 21 seminal vesicles samples obtained along with the prostate when patients underwent radical prostatectomy and prostate tissues and seminal vesicles from four organ donors. We have also studied the aneuploidy of chromosome Y in peripheral blood from four of the patients and in seminal vesicles of 11 individuals with bladder cancer (BC). The study has been performed by Fluorescence in situ hybridization (FISH) in uncultured cells. Our results indicate that complete loss of chromosome Y is found in almost all the seminal vesicles both from patients with PCa and patients with BC (samples obtained from the tissue bank), and is more frequent in prostate tumors than in nontumor samples. The percentages of chromosome Y loss in the tissues analyzed are significatively higher than expected in lymphocytes considering the patient's age as reported in the literature. The high percentage of chromosome Y loss found in the nonmalignant seminal vesicles of these patients may be an indicator of an ageing process rather than a primary cytogenetic alteration in the carcinogenesis of the prostate. However, a contribution of this loss to chromosomal instability and therefore, to the multistep tumorigenic process, cannot be discarded.     

Oesophageal adenocarcinoma: A paradigm of mechanical carcinogenesis?

Incidence of adenocarcinoma of the oesophagus and gastric cardia is increasing in most developed countries and strongly associated with obesity and male gender. An underlying increase in the prevalence of gastro-oesophageal reflux has generally been postulated. We suggest that the increase in frequency of reflux and the 2 associated forms of cancer can be explained by growing abdominal pressure brought about by increasing central obesity, most common among men, and sedentary lifestyle, including car use. Abdominal pressure is further accentuated mainly in men by the shift in Western male dressing towards the general use of belts.     

Depth of invasion in early oral cancers- is it an independent prognostic factor?

IntroductionDepth of invasion (DOI) has been incorporated into oral cancer staging. Increasing DOI is known to be associated with an increased propensity to neck metastasis and adverse tumor factors and hence may not be an independent prognosticator but a surrogate for a biologically aggressive tumor.Methods570 patients, median follow up 79.01 months from a previously reported randomized trial (NCT00193765) designed to establish appropriate neck treatment [elective neck dissection (END) vs therapeutic neck dissection (TND)] in clinically node-negative early oral cancers were restaged (nT) according to AJCC TNM 8th edition. Overall survival (OS) was estimated for the entire cohort, END, and TND arms. Multivariate analysis performed for stratification and prognostic factors, and interaction term between revised T-stage and neck treatment, for tumours with DOI≤10mm. Presence of adverse factors was compared between nT3 (DOI>10 mm) and those with DOI≤10 mm.ResultsStage migration occurred in 44.38% of patients. 5-Year OS was nT1-79%, nT2-69.4% and nT3-53.8%, (p < 0.001). In TND arm 5-year OS was nT1-81.1% versus nT2-65%,p = 0.004, while that in END arm was nT1 -76.9% versus nT2 -73.7%,p = 0.73. There was a significant interaction between T stage and neck treatment (p = 0.03). T3 tumors (>10 mm) were associated with a higher proportion of adverse factors (occult nodal metastasis, p = 0.035; LVE/PNI, p = 0.001).ConclusionElective neck treatment negates the prognostic impact of DOI for early oral cancers (T1/T2 DOI≤10 mm). T3 tumors with DOI>10 mm have a higher association with other adverse risk factors resulting in poorer outcomes in spite of elective neck dissection.     

Mosaic subclinical melanoderma: an Achilles heel for UV-related epidermal carcinogenesis?

Cutaneous cancers are not uncommon on the face of elderly patients. Melanin should protect, at least in part, against the ultraviolet (UV)-induced neoplastic damage. However, the density in melanin chromatophores is heterogeneous in the epidermis of Caucasian adults. The computerized UV light-enhanced visualization (ULEV) method is a sensitive tool to assess non-invasively this mosaic pattern of intra-epidermal melanin load. In this study, the combination of ULEV pattern analysis and image analysis were performed involving four groups of phototype III Caucasian subjects. The first group was composed of 55 patients aged from 65 to 75 years who suffered from several malignancies of facial skin. The second control group of 55 patients who never had developed skin cancers were matched with the first group for age, sex and phototype. The third group was composed of 80 patients aged from 49 to 59 years who had developed a single basal cell carcinoma. The fourth group comprised 80 age, sex and phototype-matched healthy control subjects. Irrespective of the groups of subjects, a correlation was found between the pattern grading and the objectively determined relative area of subclinical melanoderma. Patients with multiple skin cancers differed from the other groups by the fact that a significantly higher proportion of them exhibited an extensive type of subclinical melanoderma. This feature was also seen in a minority of patients with a single basal cell carcinoma. The extensive subclinical melanoderma pattern is interpreted as a clue for risk, but not as a cause of UV-induced skin carcinogenesis.     

The role of stromal fibroblasts in lung carcinogenesis: A target for chemoprevention?

The tumour microenvironment plays an essential role in the development and spread of cancers. Tumour cells interact with the surrounding extracellular matrix (ECM), embedded within which, are a variety of non‐cancer cells including cells of the vasculature, immune system and fibroblasts. The essential role of fibroblasts in the cultivation and maintenance of an environment in which tumour cells are able to maintain their aggressive phenotypic traits is becoming increasingly well documented. Cancer‐associated fibroblasts are able to secrete a vast array of ECM‐modulating factors, meaning that they have potential for a functional role in every step of the carcinogenic process. In particular, they are likely to have a role in early tumour‐initiating inflammatory events, and so may provide a potential target for chemopreventive intervention. This review summarises the known interactions between lung tumour cells and surrounding reactive fibroblasts, highlighting the need to further investigate cancer‐associated fibroblasts as therapeutic targets in lung cancer chemoprevention strategies.     

Anti-Müllerian hormone: its role in follicular growth initiation and survival and as an ovarian reserve marker

In this paper the role in the ovary of anti-Müllerian hormone (AMH), a member of the transforming growth factor-beta family of growth and differentiation factors, is reviewed. AMH has an inhibitory effect on primordial follicle recruitment and may also inhibit follicle-stimulating homone-dependent selection of follicles for dominance. In addition to its functional role in the ovary, AMH in serum is an excellent candidate marker as an indication of the ovarian reserve, not only in infertility clinic patients but also in women during and after cancer treatment.     

Does excess iron play a role in breast carcinogenesis? an unresolved hypothesis

Free iron is a pro-oxidant and can induce oxidative stress and DNA damage. The carcinogenicity of iron has been demonstrated in animal models, and epidemiologic studies have shown associations with several human cancers. However, a possible role of excess body iron stores or of elevated iron intake in breast carcinogenesis has received little attention epidemiologically. We propose that iron overload and the disruption of iron homeostasis with a resulting increase in free iron may contribute to the development of breast cancer, and we summarize the relevant evidence from mechanistic studies, animal experiments, and studies in humans. Over time a high intake of iron can lead to iron overload. Furthermore, body iron stores increase in women following menopause. Reactive oxygen species produced by normal aerobic cellular metabolism can lead to the release of free iron from ferritin. In the presence of superoxide radical and hydrogen peroxide, stored ferric iron (Fe³⁺) is reduced to ferrous iron (Fe²⁺), which catalyzes the formation of the hydroxyl radical (*OH). *OH in turn can promote lipid peroxidation, mutagenesis, DNA strand breaks, oncogene activation, and tumor suppressor inhibition, increasing the risk of breast cancer. In addition to its independent role as a proxidant, high levels of free iron may potentiate the effects of estradiol, ethanol, and ionizing radiation—three established risk factors for breast cancer. In order to identify the role of iron in breast carcinogenesis, improved biomarkers of body iron stores are needed, as are cohort studies which assess heme iron intake. Ultimately, it is important to determine whether iron levels in the breast and iron-induced pathology are higher in women who go on to develop breast cancer compared to women who do not.     

Is adjuvant radiotherapy in early stages (FIGO I-II) of epithelial ovarian cancer a treatment of the past?

External abdomino-pelvic irradiation after primary surgery in early stages of epithelial ovarian carcinoma has been used as adjuvant therapy. The aims of this study were to evaluate efficacy and tolerability of abdomino-pelvic radiotherapy in ovarian carcinomas and to find predictive factors for recurrent disease. From January 1979 to December 1993, 215 patients with FIGO stage IA-IIC epithelial ovarian carcinoma were treated with postoperative radiotherapy. Whole-abdominal irradiation or lower abdomino-pelvic irradiation were used. The dose of specification was 20 Gy to the upper part of the abdominal cavity and 40 Gy to the lower part of the abdomen and the pelvic region. Primary cure was achieved in 210 patients (98%). During the period of follow-up, 79 tumor recurrences (38%) were recorded. Abdomino-pelvic metastases were most frequent (22%). The overall 5-year and 10-year survival rate for the complete series was 60 and 41%, respectively. In a multivariate analysis, FIGO-stage, histopathological type and tumor grade were independent prognostic factors with recurrent-free survival as the end-point. Among the histopathological subtypes, the highest survival rate (80%) was found for the subgroup of 24 patients with clear cell carcinomas. Early radiation reactions of any type were noted in 85% of the cases. The incidence of severe late bowel toxicity was 12% and, in 11 patients (5%), surgery was necessary due to late radiation complications of the intestine. In conclusion, adjuvant abdomino-pelvic radiotherapy is a treatment option in early stages of ovarian carcinoma together with chemotherapy. However, further studies are needed to find the subgroup of patients who specifically might benefit from radiotherapy in this setting.