Background: Osteonecrosis of the jaw (ONJ) is a well-described complication of bisphosphonates use in patients with multiple myeloma (MM). We investigated whether the occurrence of ONJ decreased ...after the implementation of preventive measures in 128 patients with MM who received zoledronic acid.
Patients and methods: Patients with MM who received zoledronic acid were included in this analysis. Patients with a previous use of other bisphosphonates were excluded; patients were stratified into group A (n=38) and group B (n=90) if treatment was started before or after the implementation of preventive measures.
Results: One hundred and twenty-eight patients were included in this analysis. Sixteen patients (12.5%) developed ONJ—group A: 8 (26.3%), group B: 2 (6.7%) (P=0.002). The incidence rate (IR) was 0.671/100 person-months for group A and 0.230/100 person-months for group B IR ratio 2.92, P=0.029, 95% confidence interval 1.06–8.03. No patient in group B developed stage III ONJ.
Conclusion: In conclusion, the risk of developing ONJ after treatment of zoledronic acid is reduced (but not deleted) by the implementation of preventive measures.
The authors aimed to evaluate the association of the traditional Mediterranean diet and major food groups with incidence of and mortality from cerebrovascular disease (CBVD) in a Mediterranean ...population. The study population was a cohort of 23,601 participants from the Greek segment of the EPIC Study (European Prospective Investigation into Cancer and Nutrition) who were free of cardiovascular diseases and cancer at baseline (1994-1999). Diet was assessed by means of a validated food frequency questionnaire. A 10-point scale integrating key Mediterranean diet characteristics was used to assess the participants' degree of adherence to this diet. During a median follow-up period of 10.6 years (1994-2009), 395 confirmed incident cases and 196 deaths from CBVD were recorded. Using Cox proportional hazards regression and adjusting for potential confounders, increased adherence to the Mediterranean diet, as measured by 2-point increments in score, was inversely associated with CBVD incidence (adjusted hazard ratio = 0.85, 95% confidence interval: 0.74, 0.96) and mortality (adjusted hazard ratio = 0.88, 95% CI: 0.73, 1.06). These inverse trends were mostly evident among women and with respect to ischemic rather than hemorrhagic CBVD and were largely driven by consumption of vegetables, legumes, and olive oil. These data provide support for an inverse association of adherence to the Mediterranean diet with CBVD incidence and mortality.
Objective To investigate the relative importance of the individual components of the Mediterranean diet in generating the inverse association of increased adherence to this diet and overall ...mortality.Design Prospective cohort study.Setting Greek segment of the European Prospective Investigation into Cancer and nutrition (EPIC). Participants 23 349 men and women, not previously diagnosed with cancer, coronary heart disease, or diabetes, with documented survival status until June 2008 and complete information on nutritional variables and important covariates at enrolment.Main outcome measure All cause mortality.Results After a mean follow-up of 8.5 years, 652 deaths from any cause had occurred among 12 694 participants with Mediterranean diet scores 0-4 and 423 among 10 655 participants with scores of 5 or more. Controlling for potential confounders, higher adherence to a Mediterranean diet was associated with a statistically significant reduction in total mortality (adjusted mortality ratio per two unit increase in score 0.864, 95% confidence interval 0.802 to 0.932). The contributions of the individual components of the Mediterranean diet to this association were moderate ethanol consumption 23.5%, low consumption of meat and meat products 16.6%, high vegetable consumption 16.2%, high fruit and nut consumption 11.2%, high monounsaturated to saturated lipid ratio 10.6%, and high legume consumption 9.7%. The contributions of high cereal consumption and low dairy consumption were minimal, whereas high fish and seafood consumption was associated with a non-significant increase in mortality ratio.Conclusion The dominant components of the Mediterranean diet score as a predictor of lower mortality are moderate consumption of ethanol, low consumption of meat and meat products, and high consumption of vegetables, fruits and nuts, olive oil, and legumes. Minimal contributions were found for cereals and dairy products, possibly because they are heterogeneous categories of foods with differential health effects, and for fish and seafood, the intake of which is low in this population.
Dept of Clinical Therapeutics, Medical School, University of Athens, Greece. mdimop@med.uoa.gr
Osteonecrosis of the jaw (ONJ) has been associated with the use of pamidronate and zoledronic acid. ONJ ...was assessed prospectively since July 2003 in 202 patients with multiple myeloma (MM) who received bisphosphonates since April 1995. Fifteen patients (7.4%) developed ONJ. The median time of exposure to bisphosphonates was 39 months for patients with ONJ compared to 28 months (p=0.048) for patients with no ONJ. The cumulative hazard of developing ONJ was significantly higher in patients treated with zoledronic acid alone than in those treated with pamidronate alone/pamidronate+zoledronic acid/zoledronic acid+ibandronate sequentially (1% at 1 year and 15% at 4 years vs. 0% and 5%, p=0.003). In conclusion, the risk of ONJ is increased with time of exposure and probably with the use of zoledronic acid.
To investigate the effects of variable amounts of tobacco smoking on body mass index and waist-to-hip ratio among current smokers.
Population-based cohort study.
A total of 22 059 apparently healthy ...men and women, who enrolled in the Greek EPIC cohort, aged 25-84 years, who had never smoked (14 751) or were current cigarette smokers (7308).
Body mass index and waist-to-hip ratio (by anthropomentry), amount of tobacco smoking and energy expenditure (by an interviewer-administered, lifestyle questionnaire), energy intake and ethanol intake (by an interviewer-administered, validated, semiquantitative, food frequency questionnaire), at enrollment.
In comparison to nonsmokers, smokers of the average number of cigarettes have lower body mass index. Among smokers, however, increased amount of smoking tends to be positively associated with body mass index, particularly among men. Waist-to-hip ratio is positively associated with amount of cigarettes smoked per day, among both men and women.
Among smokers, tobacco smoking is positively associated with body mass index and waist-to-hip ratio. Our data suggest that the lower body mass index of smokers compared to nonsmokers reflects personality characteristics of those who choose to smoke and that the tendency to gain weight after smoking cessation may have behavioral rather than tobacco-related pharmacological roots.
Investigation of the health effects of retirement and age at retirement is limited, but the issue is particularly important given the pressure for an increase in the retirement age in Europe. In the ...Greek segment of the European Investigation into Cancer and Nutrition study, 16,827 men and women enrolled from 1994 to 1999 were either gainfully employed or had retired from such employment at enrollment; had not previously been diagnosed with stroke, cancer, coronary heart disease, or diabetes mellitus; and had complete information on important covariates and documented survival status as of July 2006. All-cause and cause-specific mortality in relation to employment status and age at retirement (among retirees) was analyzed through Cox regression models, controlling for potential confounders. In comparison to subjects still employed, retirees had a 51% increase in all-cause mortality (95% confidence interval: 16, 98). Among retirees, a 5-year increase in age at retirement was associated with a 10% decrease in mortality (95% confidence interval: 4, 15). Findings were more evident for cardiovascular than for cancer mortality, whereas, for injury mortality, there was no evidence of association. Results indicate that early retirement may be a risk factor for all-cause and cardiovascular mortality in apparently healthy persons.
Melphalan is one of the most active chemotherapeutic agents in the treatment of multiple myeloma (MM). However, the mechanism underlying differential patient responses to melphalan therapy is ...unknown.
Chromatin structure, transcriptional activity and DNA damage response signals were examined following ex vivo treatment with melphalan of both malignant bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) of MM patients, responders (n=57) or non-responders (n=28) to melphalan therapy. PBMCs from healthy controls (n=25) were also included in the study.
In both BMPCs and PBMCs, the local chromatin looseness, transcriptional activity and repair efficiency of the transcribed strand (TS) were significantly higher in non-responders than in responders and lowest in healthy controls (all P<0.05). Moreover, we found that melphalan-induced apoptosis inversely correlated with the repair efficiency of the TS, with the duration of the inhibition of mRNA synthesis, phosphorylation of p53 at serine 15 and apoptosis rates being higher in responders than in non-responders (all P<0.001).
Our findings provide a mechanistic basis for the link between DNA repair efficiency and response to melphalan therapy. Interestingly, the observation of these phenomena in PBMCs provides a novel approach for the prediction of response to anti-myeloma therapy.
The molecular pathways implicated in multiple myeloma (MM) development are rather unknown. We studied epigenetic and DNA damage response (DDR) signals at selected model loci (N-ras, p53, d-globin) in ...bone marrow plasma cells and peripheral blood mononuclear cells (PBMCs) from patients with monoclonal gammopathy of undetermined significance (MGUS; n=20), smoldering/asymptomatic MM (SMM; n=29) and MM (n=18), as well as in healthy control-derived PBMCs (n=20). In both tissues analyzed, a progressive, significant increase in the looseness of local chromatin structure, gene expression levels and DNA repair efficiency from MGUS to SMM and finally to MM was observed (all P<0.002). Following ex vivo treatment with melphalan, a gradual suppression of the apoptotic pathway occurred in samples collected at different stages of myelomagenesis, with the severity and duration of the inhibition of RNA synthesis, p53 phosphorylation at serine15 and induction of apoptosis being higher in MGUS than SMM and lowest in MM patients (all P<0.0103). Interestingly, for all endpoints analyzed, a strong correlation between plasma cells and corresponding PBMCs was observed (all P<0.0003). We conclude that progressive changes in chromatin structure, transcriptional activity and DDR pathways during myelomagenesis occur in malignant plasma cells and that these changes are also reflected in PBMCs.
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