Patrizia Carrieri

The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer.

To investigate the clinical value of somatic TP53 mutations in breast cancer, we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing. TP53 mutations were more frequent in tumors of ductal and medullar types, aggressive phenotype (high grade, large size, node positive cases, and low hormone receptor content) and in women <60 years old. TP53 mutations within exons 5 to 8 conferred an elevated risk of breast cancer-specific death of 2.27 (relative risk >10 years; P < 0.0001) compared with patients with no such mutation. The prognostic value of TP53 mutation was independent of tumor size, node status, and hormone receptor content, confirming and reconciling previous findings in smaller series. Moreover, an interaction between TP53 mutation and progesterone receptor (PR) status was revealed, TP53 mutation combined with the absence of progesterone receptor being associated with the worst prognosis. Whereas previous studies have emphasized the fact that missense mutations in the DNA-binding motifs have a worse prognosis than missense mutations outside these motifs, we show that non-missense mutations have prognostic value similar to missense mutations in DNA-binding motifs. Nonetheless, specific missense mutants (codon 179 and R248W) seem to be associated with an even worse prognosis. These results, obtained on the largest series analyzed thus far, show that TP53 mutations identified by gene sequencing have an independent prognostic value in breast cancer and could have potential uses in clinical practice.

Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy

In a sample of 277 patients included in the French APROCO cohort study who were initially adherent at follow-up visit 4 months after initiation of a protease inhibitor-containing regimen, 76.4% self-reported at least one lipodystrophy-related symptom and 30.0% failed to maintain adherence behaviour 20 months after enrolment. After multiple adjustment for other related factors, such as younger age, alcohol consumption and poor housing conditions, the number of self-reported lipodystrophy symptoms was independently associated with adherence failure.

Obesity-associated gut microbiota is enriched in Lactobacillus reuteri and depleted in Bifidobacterium animalis and Methanobrevibacter smithii

Background:Obesity is associated with increased health risk and has been associated with alterations in bacterial gut microbiota, with mainly a reduction in Bacteroidetes, but few data exist at the genus and species level. It has been reported that the Lactobacillus and Bifidobacterium genus representatives may have a critical role in weight regulation as an anti-obesity effect in experimental models and humans, or as a growth-promoter effect in agriculture depending on the strains.Objectives and methods:To confirm reported gut alterations and test whether Lactobacillus or Bifidobacterium species found in the human gut are associated with obesity or lean status, we analyzed the stools of 68 obese and 47 controls targeting Firmicutes, Bacteroidetes, Methanobrevibacter smithii, Lactococcus lactis, Bifidobacterium animalis and seven species of Lactobacillus by quantitative PCR (qPCR) and culture on a Lactobacillus-selective medium.Findings:In qPCR, B. animalis (odds ratio (OR)=0.63; 95% confidence interval (CI) 0.39–1.01; P=0.056) and M. smithii (OR=0.76; 95% CI 0.59–0.97; P=0.03) were associated with normal weight whereas Lactobacillus reuteri (OR=1.79; 95% CI 1.03–3.10; P=0.04) was associated with obesity.Conclusion:The gut microbiota associated with human obesity is depleted in M. smithii. Some Bifidobacterium or Lactobacillus species were associated with normal weight (B. animalis) while others (L. reuteri) were associated with obesity. Therefore, gut microbiota composition at the species level is related to body weight and obesity, which might be of relevance for further studies and the management of obesity. These results must be considered cautiously because it is the first study to date that links specific species of Lactobacillus with obesity in humans.

The dynamic of Adherence to highly active antiretroviral therapy : Results from the French National APROCO cohort

Objectives: Our objective was to describe the evolution of adherence to highly active antiretroviral therapy (HAART) over a 20‐month period and its relationship with virologic success. Methods: Self‐reported adherence, clinical, and virologic data were collected 4 (M4), 12 (M12), and 20 (M20) months after initiation of a protease inhibitorcontaining regimen in the French APROCO cohort. At each visit, patients were classified as nonadherent, moderately, or highly adherent, and HIV plasma RNA was determined. Results: Among the 762 patients who were regularly followed until M20, the 436 patients who answered to all questionnaires, including adherence measurement, were selected for the analysis. The proportion of highly adherent patients was 55.7%, 62.2%, and 60.3% at M4, M12, and M20, respectively. A total of 137 patients (31.4%) was “always,” 225 (51.6%) “sometimes,” and 74 (17.0%) “never” “highly adherent” during follow‐up. After multiple adjustment for known baseline predictors, virologic success after 20 months of HAART was more likely achieved in patients who were always (odds ratio [OR] 95% confidence interval [CI], 3.02 [1.64‐5.58]) or sometimes (OR [95% CI], 2.15 [1.24‐3.74]) “highly adherent.” Conclusion: Adherence behavior is a dynamic process. Continued adherence was associated with better response to therapy and should be encouraged to reduce the risk of virologic failure.

Nonadherence among HIV-infected injecting drug users: the impact of social instability.

Summary: The authors tested the impact of social instability on adherence to highly active antiretroviral therapy (HAART) among patients infected with HIV through injection drug use (IDU; MANIF2000 cohort). In the study, they analyzed sociodemographic baseline characteristics to develop an indicator of social instability. Information concerning adherence to HAART was collected through questionnaires during a 2‐year follow‐up period. Factors associated with nonadherence were studied in two different groups: 1) patients who had stopped injection drug use (ex‐IDUs) and who were not in drug maintenance programs (DMT) during the entire follow‐up period, and 2) those who were still opiate dependent. Among the 210 eligible patients, 114 were classified as ex‐IDUs and 96 as opiate dependent. Ex‐IDUs reported nonadherence behaviors in 96 of 384 visits (25.0%), while opiate‐dependent patients were nonadherent in 111 of 308 visits (36.0%; p = .02). Among ex‐IDUs, the only factor associated with nonadherence was social instability, while among opiate‐dependent patients, injection behavior was the only determinant of nonadherence behavior. For opiate‐dependent patients, DMT may enhance adherence to HAART, but only if it is successful in reducing abuse of injection practices. For ex‐IDUs, it is very important that the management of social difficulties be taken into account to increase adherence to HAART.

Health-related quality of life after 1 year of highly active antiretroviral therapy.

Objective: We investigated the impact of the first year of highly active antiretroviral therapy (HAART) on health‐related quality of life (HRQL). Methods: Medical data for patients in the French APROCO cohort were collected at enrollment (MO) and month 12 (Ml2). A self‐administered questionnaire gathered information about HRQL (Medical Outcome Study 36‐Item Short Form Health Survey) and toxicity‐related symptoms. Using the twenty‐fifth percentile of HRQL scales in the French population as a threshold, patients with normal values in at least three mental and three physical scales were considered to have a “normal HRQL.” Results: Of the 1053 patients followed through M12, HRQL data at M0 and M12 were available for 654. Among the 233 patients with a normal baseline HRQL, 63 (27.0%) experienced a deterioration of HRQL at M12. Among the 421 patients with a low baseline HRQL, 121 achieved a normal HRQL at M12. Logistic regression showed that factors independently associated with a normal HRQL at M12 were normal baseline HRQL, baseline CD4 count <500 cells/mm3, time since HIV diagnosis <8 years, undetectable HIV‐RNA at M12, and lower number of self‐reported symptoms at M12. Conclusion: An assessment of HRQL should be integrated to efficacy outcomes to evaluate and compare long‐term strategies properly and to optimize the durability of response to antiretroviral therapy.

Risk of invasive cervical cancer among women with, or at risk for, HIV infection.

Although invasive cervical cancer (ICC) has been included among the AIDS‐defining conditions since 1993, it remains controversial whether HIV infection increases the risk of developing such neoplasm. In this study, ICC risk was longitudinally investigated among 1,340 HIV‐positive intravenous drug user (IDU), 811 HIV‐negative IDU, and 801 HIV‐positive heterosexual women. These women, aged 15–49 years, were followed up at the Italian HIV Seroconverter Study, at the San Patrignano Community (Rimini, North Italy), and in South‐eastern France (the DMI‐2 study). The number of observed cases of ICC was compared with the expected one, based on ICC incidence rates among women of the same age in the general population of Italy or France, and standardized incidence ratios (SIR) were computed; 9,070 person‐years of observation were accumulated among HIV‐positive women and 2,310 among HIV‐negative ones. Ten cases of ICC were diagnosed among HIV‐positive women (SIR = 12.8): ICC risk was apparently higher among HIV‐positive IDU (SIR = 16.7) than among heterosexual women (SIR = 6.7). No cases of ICC were diagnosed among HIV‐negative IDU women admitted to the San Patrignano Community (0.15 cases were expected). Our findings confirm previous suggestions showing an increased risk of ICC among HIV‐infected women and have important implications at the individual and public health levels. Int. J. Cancer 82:334–337, 1999.

Cancer risk among men with, or at risk of, HIV infection in southern Europe.

Objective:To evaluate the cancer risk in southern European men with, or at risk of, HIV infection. Design:An analysis of longitudinal data to assess time-dependent rare events. Methods:Data from a cohort of HIV seroconverters, and from two hospital-based HIV seroprevalent cohorts were combined and analysed. The number of cancer cases observed was compared with the expected number, obtained from cancer incidence rates among men in the general population. Age-standardized incidence ratios (SIR) and their 95% confidence intervals (CI) were computed. Results:A total of 19 609 person-years of observation were accumulated among HIV-positive men, and 7957 person-years among HIV-negative men. Among HIV-positive men, statistically significant increased SIR were seen for Hodgkins disease (HD) (SIR = 8.7), liver cancer (SIR = 11.0), and cancer of the salivary glands (SIR = 33.6). An excess of lung cancer was seen among intravenous drug users (IDU), but not among homosexual men. When the risk of all non-AIDS-defining cancers was considered, HIV-positive men had a nearly twofold excess (95% CI: 1.2–2.8). A risk of similar magnitude emerged among HIV-negative IDU (95% CI: 1.0–4.5), largely attributable to lung cancer and HD. Conclusion:These findings confirm that HIV infection increases the risk of HD, whereas they suggest that the risk of hepatocellular carcinoma may also be enhanced by HIV infection. The observation of an elevated risk of lung cancer in both HIV-positive and HIV-negative IDU points to personal behaviours unrelated to HIV infection.

Health-related quality of life and patient–provider relationships in HIV-infected patients during the first three years after starting PI-containing antiretroviral treatment

The aim of this study was to investigate factors associated with better health-related quality of life (HRQL) during the first three years after starting PI-containing antiretroviral treatment. Clinical, social and behavioural data from the APROCO cohort enabled us to analyze simultaneously the association between HRQL and patients’ relationships with their health care providers. A self-administered questionnaire collected information about HRQL (MOS-SF36) and relationships with medical staff (trust and satisfaction with information). Two aggregate scores, the physical (PCS) and mental (MCS) component summaries (adjusted for baseline HRQL), were used as dependent variables in the linear regressions to identify factors associated with HRQL. We had complete longitudinal data for 360 of the 611 patients followed through M36. Factors independently associated with a high MCS were (male) gender, no more than one change in treatment, (few) self-reported symptoms and trust in the physician. Factors independently associated with high PCS levels were employment, no children, (few) self-reported symptoms and satisfaction with the information and explanations provided by the medical staff. These results underline the need to improve patient–provider relationships to optimize long-term HRQL. Socio-behavioural interventions should focus on this goal.

20 Years into the Gambia hepatitis intervention study: Assessment of initial hypotheses and prospects for evaluation of protective effectiveness against liver cancer

Primary hepatocellular carcinoma is the commonest cancer in The Gambia. The Gambia Hepatitis Intervention Study (GHIS) was established in 1986 to evaluate the protective effectiveness of infant hepatitis B immunization in the prevention of chronic liver disease, particularly, hepatocellular carcinoma and cirrhosis later in adult life. This program was designed based on a series of assumptions. Here, we used data from observational and epidemiologic studies developed since 1986 to examine the validity of these assumptions. We found that (a) hepatitis B vaccine coverage was 15% more than originally assumed, (b) protection against hepatitis B virus (HBV) infection was not dependent on the number of vaccine doses received, (c) perinatal infection with HBV was of negligible importance, and (d) the HBV attributable risk of hepatocellular carcinoma at age <50 was 70% to 80%, lower than initially assumed. Based on these data, the final outcome of the GHIS should be measurable from 2017, sooner than originally assumed. The GHIS strategy takes into account-specific patterns of virus epidemiology and natural history of hepatocellular carcinoma in Africa and provides a model for integrating and evaluating new vaccines into the Expanded Programme of Immunization of sub-Saharan African countries. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3216–24)