Antonella Zucchetto

Effect of obesity and other lifestyle factors on mortality in women with breast cancer.

A few lifestyle characteristics before cancer diagnosis have been suggested to modify the prognosis of breast cancer. Follow‐up information from 1,453 women with incident invasive breast cancer, diagnosed between 1991 and 1994 and interviewed within the framework of an Italian multicenter case‐control study, was used to assess the effect of obesity and of a large spectrum of other factors on breast cancer mortality. Five hundred and three deaths, including 398 breast cancer deaths, were identified. Hazard ratios (HR) for all‐cause and breast cancer mortality and corresponding 95% confidence intervals (CI), were calculated using Cox proportional hazards models and adjusted for age and breast cancer characteristics (stage and receptor status). Increased risk of death for breast cancer emerged for body mass index (BMI) ≥ 30 kg/m2 (HR = 1.38; 95% CI: 1.02–1.86), compared to <25, or waist‐to‐hip ratio (WHR) ≥ 0.85 (HR = 1.27; 95% CI: 0.98–1.64), compared to <0.80, and the strongest association was observed for women with BMI ≥30 and high WHR (≥0.85), compared to women with BMI <25 and WHR < 0.85 (HR = 1.57, 95% CI: 1.08–2.27). The unfavorable effect of high BMI was similar in women <55 and ≥55 years of age, whereas it was stronger in women with I–II stage than III–IV stage breast cancer. Low vegetable and fruit consumption and current or past smoking were also associated to marginally worse breast cancer survival. No significant relationship with survival after breast cancer emerged for several other major lifestyle factors, including physical activity, alcohol drinking, exogenous hormones use and fat intake. High BMI was the lifestyle risk factor that most consistently modified breast cancer prognosis in our study.

Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome

Predictors of chronic lymphocytic leukaemia (CLL) transformation to Richter syndrome (RS) are not established and were investigated in 185 consecutive CLL cases. Actuarial incidence of RS (n = 17; all diffuse large B‐cell lymphomas) at 10 years was 16·2% (95% confidence interval: 8·0–24·4%). At CLL diagnosis, prognosticators of RS by univariate analysis were IGHV homology ≥98% (P = 0·006), IGHV4‐39 usage (P < 0·001), del13q14 absence (P = 0·004), expression of CD38 (P < 0·001) and ZAP70 (P = 0·004), size (P < 0·001) and number (P < 0·001) of lymph nodes, advanced Binet stage (P = 0·002), and lactate dehydrogenase (P < 0·001). Multivariate analysis, performed separately for biological and clinical variables, identified CD38 expression [Hazard ratio (HR) = 4·26; P = 0·018], IGHV4‐39 usage (HR = 4·29; P = 0·018), and lymph node size ≥3 cm (HR = 9·07; P < 0·001) as independent RS prognosticators. A multivariate model simultaneously analysing biological and clinical variables identified lymph node size ≥3 cm (HR = 6·51; P = 0·001) and del13q14 absence (HR = 4·08; P = 0·031) as independent RS prognosticators. Risk factors of CLL transformation differed from risk factors of CLL progression. These results suggest that CD38 and del13q14 may identify biological subsets of CLL with different RS predisposition. Predominant nodal disease, CD38 expression, IGHV4‐39 usage, and absence of del13q14 may help in predicting RS at CLL diagnosis. Close monitoring and a careful biopsy policy are needed in patients carrying transformation risk factors.

The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma

BACKGROUND Obesity has been associated to increased hepatocellular carcinoma (HCC) risk, but studies on the topic do not fully account for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Likewise, an increased risk has been reported for diabetes mellitus (DM) but whether DM is an independent risk factor has not been established yet. To evaluate the association of obesity and DM with HCC risk, we conducted a hospital-based, case-control study in two Italian areas. PATIENTS AND METHODS From 1999 to 2003, 185 HCC cases and 404 hospital controls were enrolled. Blood samples were obtained for HBV and HCV screening. RESULTS After allowance for known risk factors, body mass index >/=30 kg/m(2) [odds ratio (OR) = 1.9, 95% confidence interval (CI) 0.9-3.9] and DM (OR = 3.7, 95% CI 1.7-8.4) were associated to HCC risk. These associations persisted (OR = 3.5, 95% CI 1.6-7.7 for obesity; OR = 3.5, 95% CI 1.3-9.2 for DM) among subjects without HBV and/or HCV infection. Overall, 23% of HCC cases seemed attributable to these conditions, and this figure rose to 37% among subjects without HBV and/or HCV infections. CONCLUSIONS The present study provides further evidence that obesity and DM increase HCC risk and that these factors may explain a relevant proportion of cases among subjects without markers of HBV/HCV infection.

CD38/CD31, the CCL3 and CCL4 Chemokines, and CD49d/Vascular Cell Adhesion Molecule-1 Are Interchained by Sequential Events Sustaining Chronic Lymphocytic Leukemia Cell Survival

CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38(+)CD49d(+) versus CD38(-)CD49d(-) CLL cells, we showed overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also up-regulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38(+)CD49d(+) but not CD38(-)CD49d(-) cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68(+) macrophage infiltration was particularly high in BMB from CD38(+)CD49d(+) CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express vascular cell adhesion molecule-1 (VCAM-1), the CD49d ligand, likely through tumor necrosis factor alpha overproduction. These effects were apparent in BMB from CD38(+)CD49d(+) CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1(+) stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1 transfectants increased viability of CD38(+)CD49d(+) CLL cells. Altogether, CD38 and CD49d can be thought of as parts of a consecutive chain of events ultimately leading to improved survival of CLL cells.

Stathmin activity influences sarcoma cell shape, motility, and metastatic potential

The balanced activity of microtubule-stabilizing and -destabilizing proteins determines the extent of microtubule dynamics, which is implicated in many cellular processes, including adhesion, migration, and morphology. Among the destabilizing proteins, stathmin is overexpressed in different human malignancies and has been recently linked to the regulation of cell motility. The observation that stathmin was overexpressed in human recurrent and metastatic sarcomas prompted us to investigate stathmin contribution to tumor local invasiveness and distant dissemination. We found that stathmin stimulated cell motility in and through the extracellular matrix (ECM) in vitro and increased the metastatic potential of sarcoma cells in vivo. On contact with the ECM, stathmin was negatively regulated by phosphorylation. Accordingly, a less phosphorylable stathmin point mutant impaired ECM-induced microtubule stabilization and conferred a higher invasive potential, inducing a rounded cell shape coupled with amoeboid-like motility in three-dimensional matrices. Our results indicate that stathmin plays a significant role in tumor metastasis formation, a finding that could lead to exploitation of stathmin as a target of new antimetastatic drugs.

Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: Results from an Italian multicentre study

A fraction of chronic lymphocytic leukaemia (CLL) cases carry highly homologous B‐cell receptors (BCR), i.e. characterized by non‐random combinations of immunoglobulin heavy‐chain variable (IGHV) genes and heavy‐chain complementarity determining region‐3 (HCDR3), often associated with a restricted selection of IGVK/L light chains. Such ‘stereotyped’ BCR occur more frequently in CLL with unmutated (UM) than mutated (M) IGHV genes. We analysed 1426 IG rearrangements (from 1398 CLL cases) by a clustering driven by HCDR3 similarities. Molecular findings were correlated to time‐to‐treatment (TTT) and presence of known prognosticators. Sixty‐nine clusters (319 IG‐rearrangements, 22·4%) with stereotyped BCR were identified. Among 30 confirmed clusters (≥3 IG‐rearrangements/cluster), we found 14 novel clusters, of which 11 had M IG rearrangements (M clusters) and predominantly (8/11) used IGHV3 subgroup genes. Recurrent cluster‐biased amino acid changes were found throughout IGHV sequences of these ‘M clusters’. Regarding clinical outcome: (i) UM CLL from the IGHV1‐2/1‐3/1‐18/1‐46/7‐4‐1/IGKV1‐39 cluster had poorer prognosis than UM/M cases, or UM cases using the same IGHV genes but not in clusters; (ii) M CLL from the IGHV3‐21/IGLV3‐21 cluster had TTT similar to UM CLL, and shorter than M CLL expressing IGHV3‐21 but not in cluster. Altogether, our analysis identified additional molecular and clinical features for CLL expressing stereotyped BCR.

Association between dietary inflammatory index and prostate cancer among Italian men

Previous studies have shown that various dietary components may be implicated in the aetiology of prostate cancer, although the results remain equivocal. The possible relationship of inflammation derived from dietary exposures with prostate cancer risk has not been investigated. We examined the ability of a newly developed dietary inflammatory index (DII) to predict prostate cancer risk in a case-control study conducted in Italy between 1991 and 2002. A total of 1294 patients aged < 75 years with incident, histologically confirmed carcinoma of the prostate served as cases. A total of 1451 subjects aged < 75 years who were admitted to the same hospitals as cases for a wide spectrum of acute, non-neoplastic conditions served as controls. The DII was computed based on dietary intake assessed using a previously validated seventy-eight-item FFQ. Logistic regression models were used to estimate multivariable OR adjusted for age, study centre, years of education, social class, BMI, smoking status, family history of prostate cancer and total energy intake. Men with higher DII scores had a higher risk of prostate cancer when analysed using the DII as both continuous (OR 1.06, 95% CI 1.00, 1.13) and categorical, i.e., compared with men in the lowest quartile of the DII, men in the third and fourth quartiles were at elevated risk (OR(Quartile 3 v. 1) 1.32, 95% CI 1.03, 1.69 and OR(Quartile 4 v. 1) 1.33, 95% CI 1.01, 1.76; P trend= 0.04). These data suggest that a pro-inflammatory diet, as indicated by the increasing DII score, is a risk factor of prostate cancer in Italian men.

Metabolic syndrome and endometrial cancer risk

BACKGROUND Various studies reported direct associations between endometrial cancer risk and individual components of the metabolic syndrome (MetS), i.e. obesity, diabetes, hypertension, and dyslipidemia, but only a few epidemiological studies considered the association with MetS overall. METHODS We analyzed data from a case-control study including 454 women with incident endometrial cancer and 798 controls admitted to the same hospitals as cases for acute conditions. Different definitions of MetS were considered, including a combination of self-reported history of diabetes, drug-treated hypertension, drug-treated hyperlipidemia, and various measures of (central) obesity. Odds ratios (ORs) were computed from unconditional logistic regression models, adjusted for major confounding factors. RESULTS The multivariate ORs of endometrial cancer were 2.18 for type 2 diabetes, 1.77 for hypertension, 1.20 for hyperlipidemia, between 1.62 and 2.23 for various definitions of central obesity, and 3.83 for women with a body mass index (BMI) >30 kg/m(2). The risk of endometrial cancer was significantly increased for subjects with MetS, the ORs ranging between 1.67 and 2.77 when waist circumference was included in MetS definition, and 8.40 when BMI was considered instead. CONCLUSIONS This study indicates a direct association between various MetS components, besides overweight, with the risk of endometrial cancer.

CD49d Is the Strongest Flow Cytometry–Based Predictor of Overall Survival in Chronic Lymphocytic Leukemia

PURPOSE Although CD49d is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL), definitive validation evidence is lacking. A worldwide multicenter analysis was performed using published and unpublished CLL series to evaluate the impact of CD49d as an overall (OS) and treatment-free survival (TFS) predictor. PATIENTS AND METHODS A training/validation strategy was chosen to find the optimal CD49d cutoff. The hazard ratio (HR) for death and treatment imposed by CD49d was estimated by pooled analysis of 2,972 CLLs; Cox analysis stratified by center and stage was used to adjust for confounding variables. The importance of CD49d over other flow cytometry-based prognosticators (eg, CD38, ZAP-70) was ranked by recursive partitioning. RESULTS Patients with ≥ 30% of neoplastic cells expressing CD49d were considered CD49d+. Decrease in OS at 5 and 10 years among CD49d+ patients was 7% and 23% (decrease in TFS, 26% and 25%, respectively). Pooled HR of CD49d for OS was 2.5 (2.3 for TFS) in univariate analysis. This HR remained significant and of similar magnitude (HR, 2.0) in a Cox model adjusted for clinical and biologic prognosticators. Hierarchic trees including all patients or restricted to those with early-stage disease or those age ≤ 65 years always selected CD49d as the most important flow cytometry-based biomarker, with negligible additional prognostic information added by CD38 or ZAP-70. Consistently, by bivariate analysis, CD49d reliably identified patient subsets with poorer outcome independent of CD38 and ZAP-70. CONCLUSION In this analysis of approximately 3,000 patients, CD49d emerged as the strongest flow cytometry-based predictor of OS and TFS in CLL.

Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia.

Genetic lesions and B-cell receptor (BCR) signaling are both oncogenic drivers in chronic lymphocytic leukemia (CLL). However, scant data are available on preferential associations between specific genetic alterations and stereotyped BCR subsets. By analyzing 1419 cases, 2 CLL subsets (2 and 8) harboring stereotyped BCR are enriched in specific molecular alterations influencing disease course. SF3B1 mutations are the genetic hallmark of IGHV3-21-CLL belonging to subset 2 (52%) but are evenly represented in nonstereotyped IGHV3-21-CLL. Trisomy 12 (87%) and NOTCH1 mutations (62%) characterize IGHV4-39-CLL belonging to subset 8 but occur with the expected frequency in IGHV4-39-CLL with heterogeneous BCR. Clinically, co-occurrence of SF3B1 mutations and subset 2 BCR configuration prompts disease progression in IGHV3-21-CLL, whereas cooperation between NOTCH1 mutations, +12, and subset 8 BCR configuration invariably primes CLL transformation into Richter syndrome. These findings provide a proof of concept that specific stereotyped BCR may promote or select molecular lesions influencing outcome.