M. Budroni

Pattern of cancer risk in persons with AIDS in Italy in the HAART era

A record-linkage study was carried out between the Italian AIDS Registry and 24 Italian cancer registries to compare cancer excess among persons with HIV/AIDS (PWHA) before and after the introduction of highly active antiretroviral therapy (HAART) in 1996. Standardised incidence ratios (SIR) were computed in 21951 AIDS cases aged 16–69 years reported between 1986 and 2005. Of 101u2009669 person-years available, 45u2009026 were after 1996. SIR for Kaposi sarcoma (KS) and non-Hodgkin lymphoma greatly decreased in 1997–2004 compared with 1986–1996, but high SIRs for KS persisted in the increasingly large fraction of PWHA who had an interval of <1 year between first HIV-positive test and AIDS diagnosis. A significant excess of liver cancer (SIR=6.4) emerged in 1997–2004, whereas the SIRs for cancer of the cervix (41.5), anus (44.0), lung (4.1), brain (3.2), skin (non-melanoma, 1.8), Hodgkin lymphoma (20.7), myeloma (3.9), and non-AIDS-defining cancers (2.2) were similarly elevated in the two periods. The excess of some potentially preventable cancers in PWHA suggests that HAART use must be accompanied by cancer-prevention strategies, notably antismoking and cervical cancer screening programmes. Improvements in the timely identification of HIV-positive individuals are also a priority in Italy to avoid the adverse consequences of delayed HAART use.

Incidence of thyroid cancer in Italy, 1991–2005: time trends and age–period–cohort effects

BACKGROUNDnIn Italy, some of the highest incidence rates (IRs) of thyroid cancer (TC) worldwide have been reported.nnnPATIENTS AND METHODSnTC cases <85 years of age reported to Italian cancer registries during 1991-2005 were included. Age-standardized IRs were computed for all TC and age-period-cohort effects were estimated for papillary TC.nnnRESULTSnIRs of TC were twofold higher in 2001-2005 than in 1991-1995 (18 and 8 per 100,000 women, 6 and 3 per 100,000 men, respectively). Increases were similar in the two sexes and nearly exclusively due to papillary TC. Increases of papillary TC by birth cohort were found in both sexes and among all age groups between 20 and 79 years. Age-period-cohort models showed a strong period effect in both sexes (rate ratio for 2001-2009 versus 1991-1995 = 2.5 in women and 2.3 in men), although IRs peaked at an earlier age in women (45-49 years) than men (65-69 years).nnnCONCLUSIONnThe strength of the period effect in both sexes and the earlier onset in women than men strongly implicated increased medical surveillance in the upward trends of papillary TC incidence in Italy. The consequences of the current intense search for TC on morbidity and possible overtreatment, especially among young women, should be carefully evaluated.

Cancer incidence in people with AIDS in Italy

People with HIV/AIDS (PWHA) have increased risk of some cancers. The introduction of highly active antiretroviral therapies (HAART) has improved their life expectancy, exposing them to the combined consequences of aging and of a prolonged exposure to cancer risk factors. The aim of this study was to estimate incidence rates (IR) in PWHA in Italy, before and after the introduction of HAART, after adjusting for sex and age through direct standardization. An anonymous record linkage between Italian AIDS Registry (21,951 cases) and Cancer Registries (17.3 million, 30% of Italian population) was performed. In PWHA, crude IR, sex‐ and age‐standardized IR and age‐specific IR were estimated. The standardized IR for Kaposi sarcoma and non‐Hodgkin lymphoma greatly declined in the HAART period. Although the crude IR for all non‐AIDS‐defining cancers increased in the HAART period, standardized IR did not significantly differ in the 2 periods (352 and 379/100,000, respectively). Increases were seen only for cancer of the liver (IR ratio = 4.6, 95% CI: 1.3–17.0) and lung (IR ratio = 1.8, 95% CI: 1.0–3.2). Age‐specific IRs for liver and lung cancers, however, largely overlapped in the 2 periods pointing to the strong influence of the shift in the age distribution of PWHA on the observed upward trends. In conclusion, standardized IRs for non‐AIDS‐defining cancers have not risen in the HAART period, even if crude IRs of these cancers increased. This scenario calls, however, for the intensification of cancer‐prevention strategies, notably smoking cessation and screening programs, in middle‐aged HIV‐patients.

Incidence of AIDS-defining cancers after AIDS diagnosis among people with AIDS in Italy, 1986-1998

A record linkage was carried out between the Italian National Registry of AIDS and 19 cancer registries. The aim was to evaluate the 1986 through 1998 trends in incidence rate (IR) of AIDS-defining cancers (ADCs) among persons with AIDS (PWA) in Italy overall and according to various characteristics. A steady decrease in IRs was found for Kaposi sarcoma (KS) in men between 1986–1992 (2.5 per 100 person-years [py]) and 1997–1998 (1.0 per 100 py). Conversely, the first decrease in IRs of KS in women (from 0.9 to 0.6 per 100 py) and of non-Hodgkin lymphoma in both genders (from 1.7 to 0.7 per 100 py) was seen between 1993–1996 and 1997–1998, thus pointing to a favorable impact of highly active antiretroviral therapies. The decline was consistent across different age and HIV transmission groups, but it was more marked in PWA with a CD4 count >50 cells/&mgr;L than in PWA with more severe immune suppression. As a proportion of AIDS cases, invasive cervical cancer increased from 1.5% in 1993–1996 to 2.4% in 1997–1998, but IRs after AIDS could not be evaluated. On account of the marked decline of KS in men in 1997–1998, the overall burden of ADCs in Italy became similar in both genders.

Classic Kaposi's sarcoma in Italy, 1985-1998.

To evaluate incidence rates (IRs) of classic Kaposis sarcoma (CKS) in Italy after the spread of AIDS, we distinguished CKS from AIDS-related KS (AKS) using an ‘ad hoc’ record linkage procedure between 15 Cancer Registries (CRs) (21% of the Italian population) and the national AIDS Registry. Between 1985 and 1998, 874 cases of CKS and 634 cases of AKS were diagnosed in the study areas. CKS accounted for 16 and 27% of KS cases below 55 years of age in men and women, respectively, but for 91 and 100% of those above age 55. The IRs for CKS were 1.0/ in men and 0.4/100u2009000 in women, but they varied between 0.3 in Umbria and 4.7 in Sassari in men, and between 0.1 in Parma and 1.7 in Sassari in women. IRs of CKS in both genders were stable between 1985–1987 and 1993–1998. In Northern and Central CRs the IR (adjusted for age and gender) for CKS was 0.5 in individuals born in the same area, but 1.6 in individuals born in Southern Italy or in the Islands (rate ratio=3.2) suggesting that KS-associated herpesvirus, the cause of KS, is acquired early in life.

Identification of a founder BRCA2 mutation in Sardinia

Sardinian population can be instrumental in defining the molecular basis of cancer, using the identity-by-descent method. We selected seven Sardinian breast cancer families originating from the northern-central part of the island with multiple affected members in different generations. We genotyped 106 members of the seven families and 20 control nuclear families with markers flanking BRCA2 locus at 13q12–q13. The detection of a common haplotype shared by four out of seven families (60%) suggests the presence of a founder BRCA2 mutation. Direct sequencing of BRCA2 coding exons of patients carrying the shared haplotype, allowed the identification of a ‘frame-shift’ mutation at codon 2867 (8765delAG), causing a premature termination-codon. This mutation was found in breast cancer patients as well as one prostate and one bladder cancer patient with shared haplotype. We then investigated the frequency of 8765delAG in the Sardinian breast cancer population by analysing 270 paraffin-embedded normal tissue samples from breast cancer patients. Five patients (1.7%) were found to be positive for the 8765delAG mutation. Discovery of a founder mutation in Sardinia through the identity-by-descent method demonstrates that this approach can be applied successfully to find mutations either for breast cancer or for other types of tumours.

Regional inequalities in cancer care persist in Italy and can influence survival.

BACKGROUNDnPopulation-based cancer registry studies of care patterns can help elucidate reasons for the marked geographic variation in cancer survival across Italy. The article provides a snapshot of the care delivered to cancer patients in Italy.nnnMETHODSnRandom samples of adult patients with skin melanoma, breast, colon and non-small cell lung cancers diagnosed in 2003-2005 were selected from 14 Italian cancer registries. Logistic models estimated odds of receiving standard care (conservative surgery plus radiotherapy for early breast cancer; surgery plus chemotherapy for Dukes C colon cancer; surgery for lung cancer; sentinel node biopsy for >1mm melanoma, vs. other treatment) in each registry compared to the entire sample (reference).nnnRESULTSnStage at diagnosis for breast, colon and melanoma was earlier in north/central than southern registries. Odds of receiving standard care were lower than reference in Sassari (0.68, 95%CI 0.51-0.90) and Napoli (0.48, 95%CI 0.35-0.67) for breast cancer; did not differ across registries for Dukes C colon cancer; were higher in Romagna (3.77, 95%CI 1.67-8.50) and lower in Biella (0.38, 95%CI 0.18-0.82) for lung cancer; and were higher in Reggio Emilia (2.37, 95%CI 1.12-5.02) and lower in Ragusa (0.27, 95%CI 0.14-0.54) for melanoma.nnnCONCLUSIONSnNotwithstanding limitations due to variations in the availability of clinical information and differences in stage distribution between north/central and southern registries, our study shows that important disparities in cancer care persist across Italy. Thus the public health priority of reducing cancer survival disparities will not be achieved in the immediate future.

Prognostic impact of KRAS, NRAS, BRAF, and PIK3CA mutations in primary colorectal carcinomas: a population-based study

BackgroundActivation of oncogenes downstream the EGFR gene contributes to colorectal tumorigenesis and determines the sensitivity to anti-EGFR treatments. The aim of this study was to evaluate the prognostic value of KRAS, BRAF, NRAS and PIK3CA mutations in a large collection of CRC patients from genetically-homogeneous Sardinian population.MethodsA total of 1284 Sardinian patients with histologically-proven diagnosis of colorectal carcinoma (CRC) and presenting with metastatic disease were included into the study. Genomic DNA was isolated from formalin-fixed, paraffin-embedded primary tumour tissue samples of CRC patients and screened for mutations in RAS and BRAF genes, using pyrosequencing assays, and in PIK3CA gene, using automated DNA sequencing assays.ResultsOverall, mutation rates were 35.6xa0% for KRAS, 4.1xa0% for NRAS, and 2.1xa0% for BRAF. Among available DNA samples, 114/796 (14.3xa0%) primary CRCs were found to carry a mutation in the PIK3CA gene. In this subset of patients analysed in all four genes, a pathogenetic mutation of at least one gene was discovered in about half (378/796; 47.5xa0%) of CRC cases. A mutated BRAF gene was found to steadily act as a negative prognostic factor for either time to progression as metastatic disease (from detection of primary CRC to diagnosis of first distant metastasis; pxa0=xa00.009) or partial survival (from diagnosis of advanced disease to the time of death or last control; pxa0=xa00.006) or overall survival (pxa0<xa00.001). No significant impact on prognosis was observed for mutated KRAS, NRAS, and PIK3CA genes or combined RAS mutations (all RAS).ConclusionsOur study defines both prevalence and prognostic role of main activated oncogenes in a population-based large collection of CRC patients.

Distribution of ‘promoter’ sandflies associated with incidence of classic Kaposi's sarcoma

The patchy geographical distributions of classic Kaposis sarcoma (KS) and human herpesvirus type 8 (HHV‐8), better known as Kaposis sarcoma‐associated herpesvirus (KSHV) remain unexplained. It has been proposed that certain species of bloodsucking insects (‘promoter arthropods) promote the reactivation of HHV‐8/KSHV and facilitate both HHV‐8/KSHV transmission and KS development. This hypothesis was tested by sampling the presence and density of human‐biting Diptera with CDC light traps in two areas of Sardinia with contrasting incidence rates of classic KS. In total, 11 030 specimens (99.9% sandflies and 0.1% mosquitoes) belonging to 10 species were collected from 40 rural sites. Five of these species are considered to be possible promoter arthropods because of the irritation their bites cause: Phlebotomus perniciosus Newstead; Phlebotomus perfiliewi Parrot (Diptera: Psychodidae); Aedes berlandi Seguy; Culiseta annulata (Schrank) and Culex theileri Theobald (Diptera: Culicidae). Five species are probable ‘non‐promoters because their bites are not particularly irritating: Culiseta longiareolata (Macquart); Culex pipiens s.l.; Anopheles algeriensis Theobald; Anopheles maculipennis s.l., and Anopheles plumbeus Stephens. A significant correlation was found between the geographical distribution of promoter arthropods and incidence rates of KS (Spearmans r = 0.59,P < 0.01). Promoter arthropods were more likely to be caught in areas with cutaneous leishmaniasis and a past high prevalence of malaria, and in areas of limestone, acid volcanic soil and cereal cultivation. The study supports the association between promoter arthropods and classic KS, which may explain the geographic variability of KS and HHV‐8/KSHV, and highlights the links with a number of variables previously associated with the incidence of KS.

Management of rectal cancers in relation to treatment guidelines: a population-based study comparing Italian and French patients

BACKGROUNDnFew studies have investigated rectal cancer management at the population level. We compared how rectal cancers diagnosed in Italy (2003-2005) and France (2005) were managed, and evaluated the extent to which management adhered to European guidelines.nnnMETHODSnSamples of 3938 Italian and 2287 French colorectal cancer patients were randomly extracted from 8 and 12 cancer registries respectively. Rectal cancer patients (860 Italian, 559 French) were analysed. Logistic regression models estimated odds ratios (ORs) of being treated with curative intent, receiving sphincter-saving surgery, and receiving preoperative radiotherapy.nnnRESULTSnSimilar proportions of Italian and French patients were treated with curative intent (70% vs. 67%; OR=0.92 [0.73-1.16]); the respective proportions receiving sphincter-saving surgery were 21% and 33% (OR=1.15 [0.86-1.53]). In about 50% of those treated with curative intent, ≥ 12 lymph nodes were harvested in both countries. The proportion receiving postoperative radiotherapy was higher in Italy than in France (25% vs. 11%, p<0.01), but French patients were more likely to receive preoperative radiotherapy (52% vs. 21%; OR=4.06 [2.79-5.91]).nnnCONCLUSIONnThe proportions of patients receiving preoperative radiotherapy and the numbers of lymph nodes sampled were low in both countries. Centralising treatment and potentiating screening would be practical ways of improving outcomes and adhering to guidelines.