Gender oncology: recommendations and consensus of the Italian Association of Medical Oncology (AIOM).

BACKGROUND: Following the development of gender medicine in the past 20 years, more recently in the field of oncology an increasing amount of evidence suggests gender differences in the epidemiology of cancers, as well as in the response and toxicity associated with therapies. In a gender approach, critical issues related to sexual and gender minority (SGM) populations must also be considered. MATERIALS AND METHODS: A working group of opinion leaders approved by the Italian Association of Medical Oncology (AIOM) has been set up with the aim of drafting a shared document on gender oncology. Through the 'consensus conference' method of the RAND/University of California Los Angeles (UCLA) variant, the members of the group evaluated statements partly from the scientific literature and partly produced by the experts themselves [good practice points (GPPs)], on the following topics: (i) Healthcare organisation, (ii) Therapy, (iii) Host factors, (iv) Cancer biology, and (v) Communication and social interventions. Finally, in support of each specific topic, they considered it appropriate to present some successful case studies. RESULTS: A total of 42 articles met the inclusion criteria, from which 50 recommendations were extracted. Panel participants were given the opportunity to propose additional evidence from studies not included in the research results, from which 32 statements were extracted, and to make recommendations not derived from literature such as GPPs, four of which have been developed. After an evaluation of relevance by the panel, it was found that 81 recommendations scored >7, while 3 scored between 4 and 6.9, and 2 scored below 4. CONCLUSIONS: This consensus and the document compiled thereafter represent an attempt to evaluate the available scientific evidence on the theme of gender oncology and to suggest standard criteria both for scientific research and for the care of patients in clinical practice that should take gender into account.

Oral conditions and salivary analysis in HIV-uninfected subjects using preexposure prophylaxis.

BACKGROUND: New prevention strategies have been advocated to control the progression of HIV/AIDS, such as preexposure prophylaxis (PrEP). The aim of this study is to evaluate the potential changes in the oral and salivary conditions of HIV-uninfected subjects using PrEP. MATERIAL AND METHODS: Subjects were evaluated before beginning the medication (T0), at the first follow-up (T1), and at the second follow-up (T2). Xerostomia, presence of untreated cavitated caries, oral hygiene habits, taste, gingival and plaque index, stimulated salivary flow rate (SSFR), and salivary concentrations of calcium, glucose, urea, and total proteins were evaluated. Data obtained were analyzed using statistical tests (p<0.05). RESULTS: Forty-seven participants (41 men; 6 women) were evaluated at T0. Thirty (28 men; 2 women) and 17 men were reassessed at T1 and T2, respectively. There was no difference between the SSFR and oral and salivary conditions between T0, T1, and T2 (p>0.05), except for the salivary calcium concentration, that increased at T2 compared to T1 (p=0.02). There was significant difference between taste and xerostomia at T1 (p=0.017), and the need to drink to swallow at T2 (p=0.015). There was significant correlation between the reported amount of saliva and taste (p=0.039, r=-0.378) at T1. CONCLUSIONS: The prolonged use of PrEP seems to be associated with reports of dry mouth and worsening of taste, possibly associated with increased salivary calcium concentration.

Prevalence of chondrocalcinosis in Italian subjects from northeastern Italy. The Pro.V.A. (PROgetto Veneto Anziani) study.

OBJECTIVES: To undertake an epidemiological survey of the prevalence of radiological chondrocalcinosis (CC) of the lower limbs in the elderly Italian population of the Pro.V.A. study. METHODS: Knee and pelvic basin radiographs were performed on 3099 subjects aged 65 and older, residing in the Veneto Region of Italy (Rovigo and Camposampiero areas). Two readers independently analysed the knee, coxofemoral and pubic symphysis x-rays of a consecutive sample of 1629 subjects according to Altman. Some laboratory indexes, such as serum parathyroid hormone (PTH), vitamin D (vit D), bone alkaline phosphatase (bALP), deyidroepiandrosterone (DHEA), urinary CrossLaps (XL), and inflammatory biomarkers were evaluated. Quantitative variables were summarised as mean + or - standard deviation and qualitative ones as distributions. Unpaired t-test was used to compare mean values among groups for normally distributed variables, and non-parametric Mann-Whitney test for non normal variables. RESULTS: CC was found in 169 (mean age 78.2 + or - 8.0 yrs) out of the 1629 subjects studied (10.4%). After adjusting for the sex and age structure of the target population, the prevalence was 10.0%. CC was more often observed in women than in men (M: 7.0%; F: 12.8%, p=0.0002), and increased in occurrence with age, rising from 7.8% in subjects aged 65-74 yrs, to 9.4% in those aged 75-84 yrs, and to 21.1% in subjects older than 85 yrs. The knee was the most prevalent location since it was affected in 94.1% of all the subjects with CC, in particular the right limb. Knee CC was bilateral in 71.7% of the affected patients. The occurrence of rheumatic disorders did not differ significantly between the subjects with CC and those without (rheumatoid arthritis 0.59% vs. 0.48%, p=ns). CONCLUSIONS: Although the detection of CC was limited to few joints with the knee being the most affected location, our study confirms the frequent presence of CC at different sites, in keeping with the possible role of systemic factors. Articular CC is an age-related disorder, which could partly explain the prevalence discrepancies reported by various studies. The prevalence of CC found in our survey based on standardised x-ray reading was high, suggesting that CC could be an underdiagnosed disease in the absence of radiographic investigation.

Different antioxidant profiles in Italian centenarians: the Sardinian peculiarity.

In this study, 153 Italian centenarians from four different geographical areas, including Modena (northern Italy), Ancona (central Italy), Perugia (central Italy) and Sardinia island (AKEA Project) were enrolled. Plasma levels of vitamin C, uric acid, vitamin A and vitamin E as well as the activities of superoxide dismutase and glutathione peroxidase were measured. Subjects were compared to a younger control population of the same areas, divided into three age groups:

Dialysis and kidney transplantation: similarities and differences in the psychological aspects of noncompliance.

BACKGROUND: Dialysis and kidney transplantation represent two effective strategies in treating chronic uremia, albeit with different results. Our study compared the psychological aspects of two categories of patients: patients who faced kidney transplantation and have been on dialysis, and noncompliant patients treated with these therapies. MATERIALS AND METHODS: On 170 patients (120 hemodialysis and 50 peritoneal dialysis) we used a personality analysis (MMPI2) and the COPE, which assessed the ability of patients to cope under certain conditions that can be perceived as stressful or, in any case, unusual. The screening succeeded in 11 cases among the first group and 9 in the second. Three of the 20 patients were considered to be partially noncompliant: 1 on peritoneal and the other 2 on hemodialysis. We also tested a control group of 300 people of different ages, sexes, social and cultural status, dates and kinds of transplantation (cadaveric or living donors). Of the 36 feedbacks received, only 30 were considered valuable. RESULTS: The results of the research showed that patients with less than 2 years of dialysis treatment and patients with more than 2 years survival after transplantation time were inclined to deny their disease and the possible emotions about their clinical status, drawing an inadequate attention to the difficulties. This behavior was clearer among noncompliant patients. Family problems and couple malaise in everyday life can push more and more of these patients to be noncompliant with therapeutic prescriptions, as they do not feel adequate support. The result is an excessive foreboding, poor disposition, and nervousness. CONCLUSIONS: Screening of patients' social and psychological status is useful as is psychological intervention for those who miss emotional support from the family. This psychological support is advisable for uremics who have to enter a waiting list and for those who are subject to postoperative treatment in order to promote compliant behavior.

Viabilidade celular de linfócitos como auxiliar na instituição da terapia antirretroviral na infecção pelo HIV-1 / Cellular viability of lymphocytes as an auxiliary for the institution of antiretroviral therapy in the human immunodeficiency virus infection

A infecção pelo vírus da imunodeficência humana (HIV) está associada à diminuição progressiva do número de linfócitos T CD4. Além do comprometimento na produção das células T CD4, os altos níveis de apoptose verificados nesses pacientes também são responsáveis pela depleção dessas células. O objetivo deste trabalho foi mostrar a importância da avaliação da viabilidade celular de linfócitos como auxiliar no monitoramento da infecção pelo HIV. Participaram deste estudo 18 voluntários HIV soropositivos com contagem de linfócitos CD4 ≤ 200 células/mm3 e 14 voluntários HIV soropositivos com contagem de linfócitos CD4 ≥ 200 células/mm3. O ensaio de viabilidade celular foi realizado em citômetro de fluxo, modelo FACScalliburTM. A avaliação da viabilidade celular demonstrou níveis elevados de apoptose nos pacientes HIV soropositivos com contagem de linfócitos CD4 ≤ 200 células/mm3 (64,21± 15,26), assim como nos pacientes HIV soropositivos com contagem de linfócitos CD4 ≥ 200 células/mm3 (62,63...

Y chromosome binary markers to study the high prevalence of males in Sardinian centenarians and the genetic structure of the Sardinian population.

We have analyzed a sample of 40 centenarians and 116 young controls from Sardinia, with a set of new Y chromosome binary markers, to evaluate if Y chromosome genes are involved in the high prevalence of males among centenarian Sardinians (1/2 vs. 1/4 in other populations studied). The results indicate that none of the seven lineages that account for >97% of the Y chromosome diversity in Sardinia provide an advantage with respect to the extreme longevity. However, our results, although based on the male-specific Y chromosome polymorphisms, give a clear profile of the pattern of genetic variability in Sardinia. Indeed they indicate that the Sardinian population had two main founder populations that have evolved in isolation for at least the last 5,000 years. These findings set the stage for future studies on longevity and other complex traits in Sardinia.

Systolic and pulse blood pressures (but not diastolic blood pressure and serum cholesterol) are associated with alterations in carotid intima-media thickness in the moderately hypercholesterolaemic hypertensive patients of the Plaque Hypertension Lipid Lowering Italian Study. PHYLLIS study group.

OBJECTIVE: The Plaque Hypertension Lipid Lowering Italian Study (PHYLLIS), is the first study in patients with hypertension (diastolic blood pressure (DBP) 95-115 mmHg; systolic blood pressure (SBP) 150-210 mmHg), moderate hypercholesterolaemia (LDL-cholesterol 4.14-5.17 mmol/l (160-200 mg/dl) and initial carotid artery alterations (maximum intima-media thickness (IMT) Tmax > or = 1.3 mm). The primary objective of PHYLLIS is investigating whether in these patients administration of an angiotensin converting enzyme inhibitor, fosinopril, and a statin, pravastatin, is more effective than administration of a diuretic and a lipid-lowering diet in retarding or regressing alterations in carotid IMT. While the study is in progress, baseline data are here reported to clarify the association of various risk factors with carotid IMT in these medium-high risk hypertensive patients. METHODS: Patients numbering 508 have been randomized to PHYLLIS by 13 peripheral units, in Italy. Age was (mean +/- SD) 58.4 +/- 6.7 years, males were 40.2%, current smokers 16.5%, means +/- SD of serum total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol and triglycerides concentrations were 6.79 +/- 0.67, 4.69 +/- 0.51, 1.37 +/- 0.38, 1.59 +/- 0.64 mmol/l (262.4 +/- 25.8, 181.3 +/- 19.8, 53.0 +/- 14.6, 141.0 +/- 56.7 mg/ dl). Means +/- SD of clinic sitting SBP/DBP were 159.8 +/- 9.0/98.3 +/- 4.2 mmHg. 483 of the 508 patients also had 24 h ambulatory BP monitoring, edited and read at a centralized unit (mean +/- SD 24 h SBP/DBP averages 136.3 +/- 14.1/84.0 +/- 10.0 mmHg). Quantitative B-mode ultrasound (Biosound 2000 II 5A, Biosound, Indianapolis, Indiana, USA) recordings of carotid arteries were taken by certified sonographers in the peripheral units and tracings were all read at a central unit. CBMmax (mean IMT of eight sites at common carotids and bifurcations) was 1.21 +/- 0.17; Mmax (mean of 12 sites also including internal carotids) 1.16 +/- 0.17, and Tmax (single maximum) 1.85 +/- 0.48 mm. RESULTS: Ambulatory SBP and pulse pressure (PP) (24 h, daytime, night-time averages) and their variability indices (24 h SD) were always significantly correlated with CBMmax and Mmax (P0.01 -0.001), and the correlations remained significant after adjustment for age, gender and smoking. No measurement of DBP was ever associated with any IMT measurement. Likewise, no lipid variable was found associated with any IMT measurement. CONCLUSIONS: Baseline data from PHYLLIS indicate that in this population of hypertensive patients with moderate hypercholesterolaemia, SBP and PP are with age among the most significant factors associated with carotid artery alterations. However, the narrow range of inclusion LDL-cholesterol and DBP values may have obscured an additional role of these variables.

Antiviral and antiproliferative activity in vitro of some new benzimidazole derivatives.

The antiviral and antiproliferative activity of new compounds having n-benzenesulphony 1-2 (2 or 3-pyridylethyl) benzimidazole as a base structure were studied in vitro. Their antitumour activity against human chronic myeloid leukaemia cells was evaluated and compared with that of equimolar doses of daunorubicin. Only compound 7a, with the presence of both the pyridyl moiety bound at the ethylenic bridge in C-2 of benzimidazole and the nitro-group in the benzene ring, displays a selective antiproliferative effect against certain leukaemia cells and a good antiviral activity especially towards the Coxsackie B5 virus. However, it should be noted that, in the case of hydroxybenzyl-benzimidazole, resistance also builds up to compound 7a, the Coxsackie B5 virus developing resistance to it after about ten runs. Cytotoxicity tests show that many of these substances are well tolerated by the VERO cells. The mechanism of action is still unclear.

Cytotoxicity and probable mechanism of action of sulphimidazole.

Sulphimidazole (1-methyl-2((4-aminophenyl)-sulphonyl)-amino-5-nitroimidazole) is a new compound in which a p-aminobenzenesulphonamide radical has been attached at position 2 of the 5-nitroimidazole ring. It possesses a useful spectrum of activity in vitro against various anaerobic microorganisms and its action against aerobic and facultative bacteria is synergically enhanced in association with trimethoprim. In the present study, we determined the cytotoxicity in vitro of sulphimidazole and trimethoprim, both alone and in combination, and analysed the viability of Vero cells and the protein content of their cell lysate in the presence of increasing concentrations of these drugs. Also, in order to verify the hypothesis that the action of sulphimidazole against aerobic and facultative bacteria is mediated by the sulphonamide component of the molecule, while that against anaerobic bacteria depends on the action of the nitro group of the 5-nitroimidazole ring, we studied the mechanism of action of the new compound both indirectly, by means of microbiological techniques, and directly, by determining its oxidoreduction potential with respect to that of metronidazole. The results show that sulphimidazole is only slightly toxic in vitro for Vero cells, either alone or in association with trimethoprim, and that the combination of the two functional groups in a single molecule not only maintains its structure-activity relationship intact but also broadens its antibacterial spectrum.

Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE).

Gender accounts for important differences in the incidence and prevalence of a variety of age-related diseases. Considering people of far advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In the present investigation, we report data from a nationwide study on Italian centenarians (a total of 1162 subjects), and from two studies on centenarians living in two distinct zones of Italy, i.e., the island of Sardinia (a total of 222 subjects) and the Mantova province (Northern Italy) (a total of 43 subjects). The female/male ratio was about 2:1 in Sardinia, 4:1 in the whole of Italy, and about 7:1 in the Mantova province. Thus, a complex interaction of environmental, historical and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. Gender differences in the health status of centenarians are also reported, and an innovative score method to classify long-lived people in different health categories, according to clinical and functional parameters, is proposed. Our data indicate that not only is this selected group of people, as a whole, highly heterogeneous, but also that a marked gender difference exists, since male centenarians are less heterogeneous and more healthy than female centenarians. Immunological factors regarding the age-related increase in pro-inflammatory status, and the frequency of HLA ancestral haplotypes also show gender differences that likely contribute to the different strategies that men and women seem to follow to achieve longevity. Concerning the different impact of genetic factors on the probability of reaching the extreme limits of the human life-span, emerging evidence (regarding mtDNA haplogroups, Thyrosine Hydroxilase, and IL-6 genes) suggests that female longevity is less dependent on genetics than male longevity, and that female centenarians likely exploited a healthier life-style and more favorable environmental conditions, owing to gender-specific cultural and anthropological characteristics of the Italian society in the last 100 years.

Decreased susceptibility to oxidative stress-induced apoptosis of peripheral blood mononuclear cells from healthy elderly and centenarians.

The susceptibility to undergo apoptosis of fresh human peripheral blood mononuclear cells (PBMCs) from three groups of healthy donors of different ages: young people (19-40 years), old people (65-85 years) and centenarians was assessed. Apoptosis was induced by 2-deoxy-D-ribose (dRib), an agent which induces apoptosis in quiescent PBMCs by interfering with cell redox status and mitochondrial membrane potential (MMP). Our major finding is that an inverse correlation emerged between the age of the donors and the propensity of their PBMCs to undergo dRib-induced apoptosis. PBMCs from old people and centenarians also showed an increased resistance to dRib-induced glutathione depletion and a decreased tendency to lose MMP. The anti-apoptotic molecule Bcl-2 was similarly expressed in PBMCs from the three age groups. Moreover, the plasma level of the stable product of transglutaminase, epsilon(gamma-glutamyl)lysine isodipeptide, a marker of total body apoptotic rate, was decreased in centenarians compared to young and elderly people. On the whole, these findings suggest that physiological aging is characterised by a decreased tendency to undergo apoptosis, a phenomenon likely resulting from adaptation to lifelong exposure to damaging agents, such as reactive oxygen species, and may contribute to one of the major phenomena of immunosenescence, i.e. the progressive accumulation of memory/effector T cells.

Correlation between high intake of glycyrrhizin and myolysis of the papillary muscles: an experimental in vivo study.

The ingestion of large quantities of glycyrrhizin, whether as a drug or a sweetener, is known, in susceptible subjects, to induce a syndrome similar to hypermineralcorticoidism, with bouts of hypertension, hypokaliaemia and rabdomyolysis, sometimes associated with severe renal failure and hypokaliaemia-induced arrythmias. Glycyrrhizin is also known to isomerize into the glycyrrhetic (or glycyrrhetinic) acids 18alpha- and 18beta-. In previous works, we reported that these metabolites cause bouts of hypertension and reduction in diuresis at low doses in the rat. In particular, the alpha isomer causes significant elimination of the calcium ion in the urine. The present findings confirm that 18alpha-glycyrrhetic acid is more toxic than either glycyrrhizin or the beta isomer. Histopathological study of tissue samples taken from rats treated with the alpha isomer also reveal selective damage to the myocardium with oedema, myolysis, apoptosis and blistering of the sarcoplasm. These effects begin to appear in the course of subchronic treatment, they manifest themselves in acute treatment and correlate closely with the electrocardiographic changes recorded in rats acutely treated with 18alpha-glycyrrhetic acid.

AKEntAnnos. The Sardinia Study of Extreme Longevity.

This paper describes an epidemiological study performed in all centenarians living in Sardinia, a large island located in the Mediterranean sea, 120 Km from the Italian coast. Due to its long-standing isolation, low immigration rate, high endogamy and rather uniform lifestyle, Sardinia offers an ideal setting in which to study the genetic traits associated with extreme longevity and successful aging. A total of 233 potentially eligible centenarians were traced in the entire territory. Of these, 66 died prior to being interviewed, 11 were not found and unknown, and 15 refused to be interviewed. A multidimensional home interview was administered to 141 centenarians, and an equivalent number of 60-year-old controls matched for gender and area of residence. Furthermore, 41 living siblings of the centenarians, and 41 age- and sex-matched controls for these siblings were also studied. The prevalence of centenarians was 13.56 per 100,000, and the female/male ratio was approximately 2. Prevalence and female/male ratio were consistent across the four Sardinian municipalities and are, respectively, higher and lower than those reported in other population-based surveys. A number of methodological problems confronted in doing the field work, and plans for future analysis of this rich dataset are discussed.

Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans.

Mitochondrial DNA (mtDNA) is characterized by high variability, maternal inheritance, and absence of recombination. Studies of human populations have revealed ancestral associated polymorphisms whose combination defines groups of mtDNA types (haplogroups) that are currently used to reconstruct human evolution lineages. We used such inherited mtDNA markers to compare mtDNA population pools between a sample of individuals selected for successful aging and longevity (212 subjects older than 100 years and in good clinical condition) and a sample of 275 younger individuals (median age 38 years) carefully matched as to sex and geographic origin (northern and southern Italy). All nine haplogroups that are typical of Europeans were found in both samples, but male centenarians emerged in northern Italy as a particular sample: 1) mtDNA haplogroup frequency distribution was different between centenarians and younger individuals (P=0.017 by permutation tests); and 2) the frequency of the J haplogroup was notably higher in centenarians than in younger individuals (P=0.0052 by Fisher exact test). Since haplogroups are defined on the basis of inherited variants, these data show that mtDNA inherited variability could play a role in successful aging and longevity.

[The Kern paradigm: professional independence and information demands of the scientific community]. / Il paradigma Kern: indipendenza professionale ed esigenza di informazione della comunità scientifica.

Legislative decrees 277/91 and 626/94 defined in detail role and duties of the occupational physician. There is no normative regulation about ethical principles for occupational professionals although some international organizations, such as the International Commission on Occupational Health (ICOH), are making proposals in this field. In the last decades, these principles have been assuming an increasing importance because of occupational medicine operators' major responsibility and the need of a multidisciplinary approach in work related risk prevention. The aim of this contribution is to present a case about professional independence and commercial secret that involved an occupational physician (David G. Kern), Brown University (that employees him) Memorial Hospital and a textile firm that consulted dr. Kern to investigate a pulmonary disease that affected some employees. The fact has been described by e-mail of OEM (Occupational Environmental Medicine) list. This event underlines the distance between the professional reality and ethical principles formulated in the ICOH code; these principles must be the base for a correct professional activity aiming only at promoting workers' health.

Occurrence of chronic diseases and their impact on physical disability over the whole spectrum of aging: from 65 to over 100 years of age.

The aging of the Italian population is an emerging public health priority. In 2025 Italy is expected to have the highest world median age with nearly half of the population over 50 years old. To avoid an unbearable burden of disease and disability on future generations, we must identify areas for intensive disease and disability prevention programs. Preliminary results from the PRO.V.A study show that disability is associated with conditions that are potentially preventable as chronic diseases and falls or are treatable as chronic pains. Moreover, it is of extreme interest to identify and understand biological and environmental secrets of successful aging as the AKEA study tries to do and the ways of overcoming disabilities in the extreme limits of life more and more possible to reach.

Lack of influence of apolipoprotein E4 on lipoprotein levels in the island population of Sardinia.

BACKGROUND: In this study, the apolipoprotein E (apoE) genotypes as well as plasma lipid and lipoprotein levels have been determined for the first time in 633 healthy and unrelated inhabitants on the island of Sardinia (291 men and 342 women, age range 6-89 years), randomly selected in the four districts of Sardinia among healthy people having parents and grandparents born in the same geographic area. This island lies in the centre of the western Mediterranean sea with a well-recognized peculiar and preserved genetic background. The epsilon 3 allele frequency (0.897) is higher than that previously reported in southern and mainland Italy and is one of the highest in Europe and among Caucasians; epsilon 2 allele frequency (0.040) is the lowest in Europe; epsilon 4 (0.063) is unusually low and, most interestingly, does not change in the different age groups, i.e. does not decrease in old subjects. RESULTS: Lipid and lipoprotein analysis confirm that total cholesterol and low-density lipoprotein (LDL)-cholesterol levels are lower than those described in mainland Italy; moreover, in this large Sardinian series, accurately selected, epsilon 4 allele did not influence total cholesterol (P = 0.270), LDL-cholesterol (P = 0.667) and high-density lipoprotein (HDL)-cholesterol (P = 0.549) as in other populations. In contrast, subjects carrying the epsilon 2 allele were found to have significantly lower total cholesterol (P = 0.001) and LDL-cholesterol (P = 0.001) levels than epsilon 3 carriers. CONCLUSION: The low epsilon 4 frequency and the lack of influence of this allele on lipid metabolism is a unique characteristic and, to date, has been described only in Sardinia among Caucasians; it might contribute to the low prevalence of coronary artery disease in this island.