A method to estimate mortality trends when death certificates are imprecisely coded: An application to cervical cancer in Italy

Systematic analysis of mortality trends of cervix and corpus uteri cancers is difficult in Italy, as in many other countries, because of the poor specification of uterine cancer subsites in official death statistics. The aim of this article is to propose a method for the analysis of uterine cancers mortality based on high quality incidence and prevalence data from population‐based cancer registries. The method assumes that the excess mortality of cancer patients, compared to death rates expected in the general population, is attributable to the specific cancer. The method is applied to estimate mortality trends for cancers of cervix, corpus and uterus as whole, during the period 1987–1999, in an area covered by 8 Italian cancer registries. Official mortality rates for the 2 subsites were about 60% lower than excess mortality rates, due to the very high proportion of deaths attributed to not specified subsite. Age adjusted cervical cancer excess mortality rates decreased from 3.7 to 2.7 × 100,000 women. Excess mortality for corpus uteri cancer remained approximately stable between 3 and 3.3 × 100,000 women in the period 1990–1999. The results support the efficacy of organized screening in reducing cervical cancer mortality. The same method can be used to assess mortality rates for every cancer entity identifiable in cancer registries data, not otherwise available from official death records. © 2008 Wiley‐Liss, Inc.     

A gene-environment interaction between occupation and BRCA1/BRCA2 mutations in male breast cancer?

The association of male breast cancer (MBC) with a positive breast cancer (BC) family history and with BRCA1/2 germ-line mutations points to a genetic component; a relationship with occupation has also been reported. Recently, we identified pathogenetic BRCA1/2 mutations in a population-based series of Italian MBC patients: here in, we investigated interactions between a carrier status for BRCA1/2 mutations and occupation using a case-case design and estimating case-only odds ratios (CORs). Truck-driving was the most frequent occupation (3/4 BRCA-related cases and 2/19 unrelated cases). An interaction between carrier status and working as a truck-driver emerged, when we classified MBC cases as "ever/never-held" this job title (COR 25.5; 95% Confidence Limits (CL): 1.1-1,412.5) or according to truck-driving as the "longest-held" work (COR 54.0; 95% CL: 1.6-2,997.5). The possible modifying effect on MBC risk in subjects carrying BRCA1/2 germ-line mutations of an occupation characterised by exposure to chemicals such as polycyclic aromatic hydrocarbons (PAH) that are capable of inducing DNA damage, may provide clues to the role of environmental exposures in modifying BC risk in mutation carriers in both genders.     

Clinical utility of 99mTc-Sestamibi scintimammography in the management of equivocal breast lesions

The aim of this study was to assess the utility of 99mTc-sestamibi scintimammography (SM) in patients with suspected primary or recurrent breast cancer. Forty-four (44) breast lesions (17 with suspected recurrence of disease) in 40 patients were included into the study. In these patients, the results of conventional diagnostic methods were equivocal or inconclusive. Twenty-one (21) lesions were palpable and 23 lesions were not. Histological examinations performed during the follow-up revealed malignancy in 24 specimens. SM correctly identified 21 of them, as well as 12 true negatives. There were 8 false-positive studies; therefore, the sensitivity of SM was 87.5%, specificity was 60%, positive predictive value (PPV) was 72.4%, and the negative predictive value (NPV) was 80%. The sensitivity in palpable lesions was 100%; three (3) false negatives, 1 recurrence, and 2 cancers, all of them nonpalpable. In conclusion, SM is useful in equivocal palpable lesions for resolving diagnostic uncertainty after conventional examination, and can limit the number of surgical interventions for benign disease. However, its use in nonpalpable tumors is not recommended.     

In vitro antitumour activity of resveratrol in human melanoma cells sensitive or resistant to temozolomide

Resveratrol, a polyphenol present in many plant species, exhibits a wide range of biological and pharmacological activities both in vitro and in vivo. It has been shown to exert a potent chemopreventive effect in carcinogenesis models and to induce cell growth inhibition and apoptosis in human tumour cells, including melanoma cells. Malignant melanoma is considered to be a chemotherapy-refractory tumour, and the commonly used anticancer drugs do not seem to modify the prognosis of metastatic disease. To further evaluate the therapeutic potential of resveratrol in the treatment of melanoma, we selected three human melanoma cell lines with different levels of resistance to temozolomide (TMZ), an antitumour triazene compound. The cell lines were subjected to resveratrol treatment and analysed for cell growth inhibition, cell cycle perturbation and apoptosis induction. We found that resveratrol markedly impaired proliferation of both the TMZ-sensitive M14 and the TMZ-resistant SK-Mel-28 and PR-Mel cell lines. The latter cell line was two-fold more resistant to the drug than M14 and SK-Mel-28 cells. The sensitivity of normal human keratinocytes to resveratrol was found to be significantly higher than that of M14 and SK-Mel-28 cells and similar to that of the PR-Mel cell line. This suggests a possible good in vivo therapeutic index for resveratrol. Our results also show that the growth-inhibitory effect of resveratrol on melanoma cells is mainly due to its ability to induce S-phase arrest and apoptosis. Taken together, our data indicate that resveratrol is an interesting candidate for the treatment of advanced melanoma.     

In vitro biofilms and antifungal susceptibility of dermatophyte and non‐dermatophyte moulds involved in foot mycosis

Tinea pedis and onychomycosis are among the commonest fungal diseases in the world. Dermatophytes and, less frequently, non‐dermatophyte moulds are aetiological agents of foot mycosis and are capable of forming biofilms. Fungal biofilm has demonstrated increasing drug resistance. This work aims to evaluate, in vitro, the ability to form biofilm and the susceptibility to antifungal drugs of sessile dermatophytes and non‐dermatophyte moulds involved in foot mycosis. Thirty‐six dermatophytes and non‐dermatophyte moulds isolated from Tunisian patients with foot mycoses, and identified with MALDI ‐TOF have been tested. MIC s of fluconazole, econazole, itraconazole, terbinafine and griseofulvin were carried out using CLSI broth microdilution method. The ability to form biofilm and antifungal activities of drugs against fungal biofilm formation has been quantified by Crystal Violet and Safranin Red staining. Biomass quantification revealed that all species studied were able to form biofilms in vitro after 72 hours. Fluconazole, econazole, itraconazole and terbinafine inhibited fungal growth with MIC values ranging from 0.031 to >64 μg mL^?1. The best antifungal activity has been obtained with terbinafine against Fusarium solani . Econazole showed the highest activity against fungal biofilm formation. These findings can help clinicians to develop the appropriate therapy of foot mycosis.     

DNA damage in tissues of rat treated with potassium canrenoate

Potassium canrenoate (PC), a competitive aldosterone antagonist previously found to increase tumor incidence in rats and to produce genotoxic effects in in vitro systems, was examined in rats to acquire information on its genotoxic activity in vivo. Intragastric administration of 1/2 LD50 produced, as revealed by the Comet assay, a modest but statistically significant increase in the frequency of DNA lesions in liver but not in thyroid and bone marrow of male rats, and in thyroid and bone marrow but not in liver of female rats. In contrast with the frankly positive responses observed in primary cultures of rat hepatocytes (Martelli et al., Mutagenesis 14 (1999) 463-472) any evidence of DNA repair and micronuclei formation was absent in liver of rats treated with 1/2 LD50, and initiation of enzyme-altered liver preneoplastic lesions did not occur in the liver of rats given 100 mg/kg PC once a week for 6 successive weeks. A high and dose-dependent frequency of DNA lesions was found to occur in testes and ovaries of rats given single doses ranging from 1/8 to 1/2 LD50.     

Combined inhibition of Chk1 and Wee1 as a new therapeutic strategy for mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive, incurable disease, characterized by a deregulated cell cycle. Chk1 and Wee1 are main regulators of cell cycle progression and recent data on solid tumors suggest that simultaneous inhibition of these proteins has a strong synergistic cytotoxic effect. The effects of a Chk1 inhibitor (PF-00477736) and a Wee1 inhibitor (MK-1775) have been herein investigated in a large panel of mature B-cell lymphoma cell lines. We found that MCL cells were the most sensitive to the Chk1 inhibitor PF-00477736 and Wee1 inhibitor MK-1775 as single agents. Possible involvement of the translocation t(11;14) in Chk1 inhibitor sensitivity was hypothesized. The combined inhibition of Chk1 and Wee1 was strongly synergistic in MCL cells, leading to deregulation of the cell cycle, with increased activity of CDK2 and CDK1, and activation of apoptosis. In vivo treatment with the drug combination of mice bearing JeKo-1 xenografts (MCL) had a marked antitumor effect with tumor regressions observed at non-toxic doses (best T/C%=0.54%). Gene expression profiling suggested effect on genes involved in apoptosis. The strong synergism observed by combining Chk1 and Wee1 inhibitors in preclinical models of MCL provides the rationale for testing this combination in the clinical setting.     

Radiation-Related Deregulation of TUBB3 and BRCA1/2 and Risk of Secondary Lung Cancer in Women With Breast Cancer

IntroductionBreast cancer survivors are at increased risk of developing unrelated primary cancers, particularly lung cancer. Evidence indicates that sex hormones as well as a deregulation of DNA-repair pathways may contribute to lung cancer onset. We investigated whether the hormone status and expression of markers involved in DNA repair (BRCA1/2, ERCC1, and P53R2), synthesis (TS and RRM1), and cell division (TUBB3) might be linked to lung cancer risk.Patients and MethodsThirty-seven breast cancer survivors with unrelated lung cancer and 84 control subjects comprising women with breast cancer (42/84) or lung cancer (42/84) were enrolled. Immunohistochemistry on tumor tissue was performed. Geometric mean ratio was used to assess the association of marker levels with patient groups.ResultsEstrogen receptor was expressed in approximately 90% of the breast cancer group but was negative in the majority of the lung cancer group, a result similar to the lung cancer control group. Likewise, ER isoform β was weakly expressed in the lung cancer group. Protein analysis of breast cancer versus control had a significantly lower expression of BRCA1, P53R2, and TUBB3. Likewise, a BRCA1 reduction was observed in the lung cancer group concomitant with a BRCA2 increase. Furthermore, BRCA2 and TUBB3 increased in ipsilateral lung cancer in women who had previously received radiotherapy for breast cancer.ConclusionThe decrease of DNA-repair proteins in breast cancer could make these women more susceptible to therapy-related cancer. The increase of BRCA2 and TUBB3 in lung cancer from patients who previously received radiotherapy for breast cancer might reflect a tissue response to exposure to ionizing radiation.     

Flavonoid and lignan intake and pancreatic cancer risk in the European prospective investigation into cancer and nutrition cohort

Despite the potential cancer preventive effects of flavonoids and lignans, their ability to reduce pancreatic cancer risk has not been demonstrated in epidemiological studies. Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 865 exocrine pancreatic cancer cases occurred after 11.3 years of follow‐up of 477,309 cohort members. Dietary flavonoid and lignan intake was estimated through validated dietary questionnaires and the US Department of Agriculture (USDA) and Phenol Explorer databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using age, sex and center‐stratified Cox proportional hazards models, adjusted for energy intake, body mass index (BMI), smoking, alcohol and diabetes status. Our results showed that neither overall dietary intake of flavonoids nor of lignans were associated with pancreatic cancer risk (multivariable‐adjusted HR for a doubling of intake = 1.03, 95% CI: 0.95–1.11 and 1.02; 95% CI: 0.89–1.17, respectively). Statistically significant associations were also not observed by flavonoid subclasses. An inverse association between intake of flavanones and pancreatic cancer risk was apparent, without reaching statistical significance, in microscopically confirmed cases (HR for a doubling of intake = 0.96, 95% CI: 0.91–1.00). In conclusion, we did not observe an association between intake of flavonoids, flavonoid subclasses or lignans and pancreatic cancer risk in the EPIC cohort.     

Role of Aromatic Herbs and Spices in Salty Perception of Patients with Hyposmia

Herbs and spices represent a possibility for the improvement of anosmia and ageusia. In this work we evaluated the role of Mediterranean aromatic herbs and spices in the salty taste perception of patients with hyposmia compared to healthy controls. To this goal, the salty taste perception in response to pure salt and different types of commercial flavored sea salt was assessed in patients with hyposmia, with or without a post-acute coronavirus syndrome, and healthy controls. Myrtle berries and leaves, a mixture of Mediterranean herbs and plants such as helichrysum, rosemary, liquorice, fennel seeds and myrtle leaves, oranges and saffron were used as salt flavoring ingredients. Differences in gustatory perception between 57 patients with hyposmia and 91 controls were evaluated considering the rate of the gustatory dimensions of pleasantness, intensity, and familiarity, using a 7-point hedonic Likert-type scale. At a dose of 0.04 g/mL, saline solutions of flavored salts, with an average 15% less NaCl, were perceived by patients with hyposmia as equally intense but less familiar than pure salt solution, with similar scores in the pleasantness dimension. Our study highlighted the central role of Mediterranean aromatic plants in the enhancement of salty perception in patients with hyposmia.