Survival of hepatocellular carcinoma patients is significantly improving: a population-based study from southern Switzerland.

BACKGROUND: During the last 20 years, relevant diagnostic procedures and advanced treatments have been progressively introduced in the management of hepatocellular carcinoma (HCC). The aim of the present study was to assess up-to-date survival trends for HCC in southern Switzerland, a region with one of the highest incidence rates in the country. METHODS: HCCs diagnosed in 1996-2009 were selected by the Ticino Cancer Registry. Cancer-specific survival (CSS) analysis was performed using the Kaplan-Meier method by calendar period: 1996-2000, 2001-2005 and 2006-2009. The log-rank test was used to detect differences in survival curves. Simultaneous assessment of prognostic factors was performed by a multivariate analysis using the Cox proportional-hazards regression model. RESULTS: 619 HCCs were analysed. There was a significant increase of patients undergoing transarterial chemoembolisation (TACE), whereas patients undergoing curative or palliative supportive treatments remained unchanged (p < 0.0001). No shift to earlier stages was detected. Significant differences in CCS were observed by age-group (p < 0.0001), diagnosis period (p < 0.0001), diagnosis technique (p = 0.0035), Barcelona-Clinic liver cancer stage (p < 0.0001), treatment (p < 0.0001). Multivariate analysis confirmed the independent impact on CSS of factors above mentioned, not including the diagnosis technique. Death risk was higher for patients diagnosed in 1996-2000 (HR: 1.32; 95% CI: 1.03; 1.68) and 2001-2005 (HR: 1.33; 95% CI: 1.05; 1.67) in comparison with 2006-2009 (reference group). CONCLUSIONS: The current population-based report describes a major increase in HCC survival. Simultaneously an increased use of TACE has been detected, probable cofactor of the observed survival increase. Possibly additional efforts could be made to decrease the HCC stage at diagnosis through active surveillance of cirrhotic patients to allow an increase in curative treatments. For sure efforts should be made to comply with a standardised staging system for HCC, particularly for comparative population-based issues.

Opportunistic screening strategy for cutaneous melanoma does not change the incidence of nodular and thick lesions nor reduce mortality: a population-based descriptive study in the European region with the highest incidence.

The aim of the present population-based descriptive study was to evaluate the incidence and mortality trends for melanoma to gain insights on the effectiveness of opportunistic secondary prevention strategies. Data on all invasive cutaneous melanoma cases occurring between 1996 and 2011 were retrieved from the Ticino Cancer Registry, southern Switzerland. The European age-standardized incidence rates were computed by the period of diagnosis, Breslow thickness and histological types. Trends in incidence and mortality rates were measured as the annual per cent change (APC). A total of 1230 patients had a diagnosis of invasive cutaneous melanoma. Cases were categorized as follows: superficial spreading melanoma (55.7%), nodular melanoma (10.0%), lentigo maligna melanoma (5.5%), melanoma not otherwise specified (25.2%) and other types (3.6%). The incidence rate of invasive melanoma rose from 17.4 per 100,000 inhabitants in 1996-2003 to 20.6 in 2004-2011, with an overall APC of +2.1% [95% confidence interval (CI): -0.8%, +5.1%]. An increase in incidence was observed for superficial spreading melanoma (APC = +2.9%; 95% CI: -1.1%, +7.0%) and thin melanomas (i.e. ≤ 1.00 mm) (APC = +3.4%; 95% CI: +0.2%, +6.7%), whereas we detected a descriptive growing incidence of thick melanomas (APC = +2.1%; 95% CI: -1.4%, +5.8%). Mortality trend analysis revealed constant rates throughout the study period (APC = -1.0%; 95% CI: -5.5%, +3.7%). This population-based study confirms that in a country with the highest incidence of cutaneous melanomas, that is, Switzerland, the opportunistic screening strategy does not change the incidence of thick melanomas nor the overall mortality. This study suggests there is still a need for public health efforts in primary and secondary prevention.

Impact of preoperative radiotherapy on survival in locally advanced rectal cancer: an observational population-based study from the South of Switzerland.

Preoperative radiotherapy (RT) followed by surgery is widely accepted in the treatment of locally advanced rectal cancer (LARC). This study aimed to estimate at the population-based level the impact of preoperative RT on overall survival (OS) and cancer-specific survival (CSS) in LARCs diagnosed in Southern Switzerland between 1996 and 2007. All patients with LARC were selected from the Ticino Cancer Registry database. Patients were categorized according to the first administered treatment: preoperative radiotherapy (RT) followed by surgery (RT+) versus surgery (RT-). Clinical-pathological characteristics and 5-year OS and CSS were analysed. Among 384 patients with LARC, 54% underwent preoperative RT, occurring more frequently in the mid-distal part of the rectum compared with the RT- group (74.8 vs. 29.8%, respectively). Both 5-year OS and CSS significantly improved in RT+ patients (OS: 68 vs. 54%, respectively; CSS: 71 vs. 63%, respectively). The adjusted hazard ratio for all death was equal to 0.66 (95% confidence interval: 0.46; 0.97); similarly, the hazard ratio for cancer-specific death was 0.63 (95% confidence interval: 0.39; 0.99). These observational population-based results, after controlling for most important diagnostic and clinical prognostic factors, confirm the benefit of preoperative RT of LARC, even if the magnitude seems greater than expected in clinical trials results. Additional studies are needed, particularly with regard to the possible effect of standardized staging procedure and multidisciplinary discussion on patient outcome.

Epidemiology and molecular biology of gastrointestinal stromal tumors (GISTs): a population-based study in the South of Switzerland, 1999-2005.

Introduction. Gastrointestinal stromal tumors (GISTs) are characterized at the molecular level by c-kit or PDGFRA oncogene mutations. Although GISTs raised major interest in past decades, population-based studies are still rare. Materials and Methods. All GISTs diagnosed in Southern Switzerland (1999-2005) were identified using Ticino Cancer Registry and analysed for c-kit and PDGFRA mutations. Clinical and molecular features were studied. Results. Annual incidence of GISTs was 1.47 cases/100,000 inhabitants (median age: 64 years; median size: 6.0 cm). Most GISTs arose in the stomach (60.5%). The malignancy risk was very-low/low in 47% of patients. DNA sequences showed a gene alteration in either c-kit or PDGFRA genes in 72.5% of patients. Mutations occurred mostly in c-kit exon 11 (60%). No mutations in c-kit exons 13 or 17 were found. An equal number of alterations in exons 12 and 18, and no mutations in exon 14 were observed in the PDGFRA gene. Discussion. This is the first comprehensive population-based study of GISTs incidence and molecular biology characterization in Central Europe. Our incidence data showed higher age-standardized rates compared to other European countries. The gene mutation spectrum differed when compared to the literature. This is relevant to improve the molecular profile knowledge based on Cancer Registry data.

Expression of receptor for advanced glycation end products in sarcoid granulomas.

RATIONALE: The receptor for advanced glycation end products (RAGE) engages a number of ligands implicated in inflammatory processes. The RAGE coding gene maps to the 6p21.32 region, close to the genes DRB1 and BTNL2, which are associated with sarcoidosis. OBJECTIVES: We investigated a possible implication of RAGE in sarcoid granulomas. METHODS: RAGE and major ligands (N-epsilon-carboxy-methyl-lysine [CML], S100A12, and S100B) expression was investigated by immunostaining of 99 paraffin-embedded biopsies of sarcoid tissues, and expression patterns were determined. Among the three RAGE gene single-nucleotide polymorphisms investigated, -374 T/A was selected, characterized in terms of transcriptional effect (immunocytochemistry and real-time polymerase chain reaction), and its frequency was determined in DNA extracted from biopsies. MEASUREMENTS AND RESULTS: RAGE, CML, S100A12, and S100B immunoreactivity was observed in all sarcoid granulomas, although at different intensities. The degree of RAGE expression significantly correlated with the degree of S100A12 expression. The -374 TT/AT genotypes, associated with higher RAGE transcriptional activity, were more frequent in the sarcoidosis biopsy group than in control subjects, and the association was confirmed in a second, independent series of 101 patients with sarcoidosis. CONCLUSIONS: We showed the association of RAGE and its ligands with sarcoidosis and suggest that an intrinsic genetic factor could be in part involved in its expression. In Italian patients, the -374 T/A polymorphism seems to be significantly associated with this disease.

NOD2/CARD15 gene polymorphisms in idiopathic pulmonary fibrosis.

BACKGROUND: Micro-organisms, behaving in a non-infectious fashion, may be among the exogenous factor(s) believed to trigger idiopathic pulmonary fibrosis (IPF). One possible strategy to identify an individual's susceptibility to such microbial triggers, which are likely to be ubiquitous, is to investigate the molecular processes involved in their recognition. NOD2/CARD15 is a specific pattern recognition receptor protein, whose genetic variants have been previously associated with susceptibility to Crohn's disease. AIM: The aim of this work was to determine the frequencies of the three major NOD2/CARD 15 gene mutations (R702W, G908R and 1007fsinC) in a series of 76 subjects affected by IPF, and to compare them with those found in three groups of controls: a group with sarcoidosis (a disorder in which an involvement of the NOD2/CARD15 gene has already been investigated and rejected in different ethnic groups; 67 subjects) and two groups of healthy subjects (218 and 208 subjects, respectively), matched for gender, age, and ethnicity. RESULTS: We found no differences in frequencies of NOD2/CARD15 gene polymorphisms among the four groups investigated. CONCLUSION: We conclude that the NOD2/CARD15 gene is not likely to be involved in susceptibility to IPF in Italians.

Identification of a novel alpha1-antitrypsin null variant (Q0Cairo).

Alpha1-antitrypsin deficiency (AATD) is a common hereditary disorder associated with high risk of developing pulmonary emphysema early in life and, to a lesser extent, chronic liver disease and cirrhosis. Among Northern Europeans and Northern Americans, more than 95% of individuals with emphysema associated with AATD carry the most frequent AAT deficient gene variants, PI*Z and PI*S. Rare AAT deficient variants account for 2-4% of AATD individuals. We extend the sequence data on AAT by characterizing a novel Null allele detected in 3 subjects: a carrier belonging to an Italian/Egyptian family and 2 members of a family originating from Southern Italy. The mutation raised on a M1 (Ala213) base allele and it is characterized by an A-->T transversion at exon III, nt 218, codon 259 (AAA-->TAA) (GeneBank accession number AY 256958). The transversion results in a premature stop codon (Lys259AAA-->Stop259TAA). The proposed nomenclature of Q0cairo is from the birthplace of the father of first recognized subject. Serum levels and isoelectric focusing of AAT were consistent with the presence of the Null variant.

A novel method for rapid genotypic identification of alpha 1-antitrypsin variants.

There is worldwide growing awareness of alpha 1-antitrypsin deficiency (AATD), a major hereditary disorder in Caucasians. The gold standard for laboratory diagnosis of AATD is thin-layer isoelectrofocusing (IEF), which is labor intensive and should be performed in reference laboratories. The aim of this study was to find an easy, fast, and cheap method for detecting alpha1-antitrypsin S and Z variants, the most frequent variants associated with AATD. The novel method herein described is based on SexAI/Hpy99I RFLP. We studied samples from 90 subjects enrolled in the Italian National Registry for AATD, previously typed by isoelectrofocusing. We found a complete agreement among our results, IEF, and genotypes obtained by standard methods. We concluded that this novel method combines efficiency, ease, swiftness, and low cost.

Langerhans cells beta 2-adrenoceptors: role in migration, cytokine production, Th priming and contact hypersensitivity.

We showed that norepinephrine (NE) hampers IL-12 and stimulates IL-10 production via adrenoceptors (ARs) in bone marrow-derived dendritic cells (BMDC) influencing their Th priming ability. Others have shown that Langerhans cells (LC) express mRNA for beta1-, beta2- and alpha1(A)-(ARs) and that catecholamines may inhibit the antigen-presenting capability via beta2-ARs. Here, we show that also BMDC express mRNA for beta1-, beta2-, alpha2(A)- and alpha2(C)-ARs. Inhibition of IL-12 is mediated by both beta2- and alpha2(A)-ARs, while stimulation of IL-10 by beta2-ARs only. In addition, LC migration, the contact hypersensitivity response (CHS) and production of IFN-gamma and IL-2 in draining lymph node cells is increased in mice treated topically with the beta2-AR antagonist ICI 118,551 during FITC sensitization. Activation of beta2-ARs in BMDC before adoptive transfer could reduce both migration and CHS response to FITC. Finally, preincubation of BMDC with LPS in presence of the specific beta2-AR agonist salbutamol impaired their chemotactic response to CCL19 and CCL21 and this effect was neutralized by anti-IL-10 mAb. We suggest that the physiological activation of beta2-ARs in DC (LC) results in stimulation of IL-10 which in turn restrains DC (LC) migration influencing antigen presentation and the consequent CHS response.