Publications

The protocol has been registered (NCT01785537) and approved by the Ethics Committee of the University of Chieti (Record n. 6; 25-03-2013).

Phenobarbital is not genotoxic, but has been related to promotion of liver cancer (as well as inhibition) in rodents. In October 2012, we carried out a systematic literature search in the Medline database and searched reference lists of retrieved publications. We identified 15 relevant papers. Epidemiological data on epileptics/anticonvulsant use and liver cancer were retrieved from eight reports from seven cohort (record linkage) studies of epileptics, and data on phenobarbital use from a pharmacy-based record linkage investigation of patients treated with phenobarbital (three reports), plus a case-control study nested in one of the cohort studies and including information on phenobarbital use. Of the studies of cancer in epileptics, two showed no excess risk of liver cancer. A long-term (1933-1984) Danish cohort study of epileptics found relative risks (RRs) of 4.7 [95% confidence interval (CI) 3.2-6.8] of liver cancer and of 2.2 (95% CI 1.2-3.5) of biliary tract cancers. Such apparent excess risks could, however, be largely or completely attributed to thorotrast, a contrast medium used in the past in epileptic patients for cerebral angiography. A Finnish cohort study of epileptics obtained an RR of 1.7 (95% CI 1.2-2.4). Such an apparent excess risk, however, was not related to phenobarbital or to any specific anticonvulsant drug. The long-term follow-up of two UK cohorts found some excess risk of liver cancer among severe, but not among mild, epileptics. Some excess risk of liver cancer was also found in cohort studies of patients hospitalized for epilepsy in Sweden and Taiwan, in the absence, however, of association with any specific drugs. A UK General Practice database, comparing epileptics treated with valproate with unexposed ones, found a very low incidence of liver cancer. Of the studies of cancer in patients treated with phenobarbital, a large US pharmacy-based cohort investigation showed no excess risk of liver cancer. In a case-control study, nested in the Danish cohort of epileptics, no association was observed between phenobarbital and liver cancer among patients who had not received thorotrast (RR=1.0 for liver and 0.8 for biliary tract cancers). Thus, some, although not all, studies reported excess risk of all cancers and liver cancer in severe, but not in milder epileptics. There is no evidence of a specific role of phenobarbital in human liver cancer risk, but data on the topic are limited.

The assessment of risk factors in cancer etiology is necessary for defining optimal preventive strategies, as well as for identifying high risk individuals, and it is therefore relevant for medical practice and cancer prevention. The Stomach cancer Pooling (StoP) Project is a consortium of epidemiological studies of gastric cancer (GC), established in year 2012. The StoP Project aims to examine the role of lifestyle, environmental and genetic determinants of GC through pooled analyses of subject-level data. The consortium is the major GC dataset globally, including original data from 35 studies – with case–control study design, including 5 nested case–control within cohort studies – conducted in the Americas, Asia and Europe (Table 1), for a total of about 13,500 cases and 32,000 controls, and it is continuously expanding. To date, the StoP Project contributed a detailed quantification of the risk of GC associated to several factors, including cigarette smoking (relative risk, RR, of 1.32 for heavy vs. never smokers), alcohol drinking (RR=1.48 for heavy vs. never drinkers), socio-economic status (RR=0.60 for high vs. low education), selected dietary factors (RR=1.30 for high vs. low meat intake; RR=0.65 for high vs. low vegetables consumption; RR=0.80 for high vs. low citrus fruit; RR=0.67 for high vs. low polyphenols intake) and occupational exposures (RR=1.70 for miners; RR=1.30 for construction workers; RR=1.33 for agricultural and animal husbandry workers; RR=1.41 for blacksmiths and machine-tool operators). Planned future developments are to analyze the role of rare exposures on GC risk and to examine risk factors in understudied patient subgroups (e.g., young onset GC, gastric cardia cancer, etc.); to integrate additional studies from East Asia; to develop a genome-wide modeling of polygenic risk score in GC; to include survival analyses and to apply machine learning methods in GC risk prediction and prognostication. Table 1 - Studies included in the StoP Project (at 13-05-2021) # Study area(s) Period Study type Reference 1 Milan, Italy 1985-1997 Case-control, hospital-based (La Vecchia et al., 1995) 2 Harbin, China 1987-1989 Case-control, hospital-based Hu (Deandrea et al., 2010) 3 Milan, Italy 1997-2007 Case-control, hospital-based (Pelucchi et al., 2009) 4 Rome, Italy 2006-ongoing Case-control, hospital-based (De Feo et al., 2012) 5 4 areas, Italy 1985-1987 Case-control, population-based (Buiatti et al., 1989) 6 Athens, Greece 1981-1984 Case-control, hospital-based (Lagiou et al., 2004) 7 8 provinces, Canada 1994-1997 Case-control, population-based (Mao et al., 2002) 8 Taixing, Jiangsu, China 2000 Case-control, population-based (Mu et al., 2005) 9 Moscow, Russia 1996-1997 Case-control, hospital-based (Zaridze et al., 1999) 10 Ardabil, Iran 2004-2005 Case-control, population-based (Pourfarzi et al., 2009) 11 Ardabil, Iran 2005-2007 Case-control, population-based (Pakseresht et al., 2011) 12 Shanghai, Qingdao, China 1991-1993 Case-control, population-based (Setiawan et al., 2005) 13 Yangzhong, China 1995 Case-control, population-based (Setiawan et al., 2001) 14 New York, USA 1992-1994 Case-control, hospital-based (Zhang et al., 1999) 15 New York, USA 1980-1990 Case-control, hospital-based Unpublished data 16 Porto, Portugal 1999-2006 Case-control, population-based (Lunet et al., 2007) 17 2 counties, Sweden 1998-2010 Cohort, nested case-control (SMC study) (Harris et al., 2013) 18 Ardabil, Iran 2001-2004 Case-control, hospital-based (Derakhshan et al., 2008) 19 2 counties, Sweden 1998-2010 Cohort, nested case-control (COSM study) (Harris et al., 2013) 20 10 provinces, Spain 2008-2012 Case-control, population-based (Castaño-Vinyals et al., 2015) 21 5 counties, Sweden 1989-1995 Case-control, population-based (Ye et al., 1999) 22 Valencia, Spain 1995-1999 Case-control, hospital-based (Santibanez et al., 2012) 23 Mexico City, Mexico 2004-2005 Case-control, population-based (Hernández-Ramírez et al., 2009) 24 Mexico City, Mexico 1989-1990 Case-control, population-based (López-Carrillo et al., 1994) 25 3 areas, Mexico 1994-1996 Case-control, hospital-based (López-Carrillo et al., 2003) 26 Sao Paulo, Brazil 1991-1994 Case-control, hospital-based (Brazilian residents) (Nishimoto et al., 2002) 27 Sao Paulo, Brazil 1991-1994 Case-control, hospital-based (Japanese residents) (Hamada et al., 2002) 28 Nagano, Japan 1998-2002 Case-control, hospital-based (Machida-Montani et al., 2004) 29 Riga, Latvia 2007-ongoing Case-control, hospital-based (Leja et al., 2017) 30 Nebraska, USA 1988-1993 Case-control, population-based (Ward et al., 1997) 31 Greece 1994-1999 Cohort, nested case-control (EPIC study) (Psaltopoulou et al., 2008) 32 Finland 1985-1988 Cohort, nested case-control (ATBC study) (Ann Epidemiol 1994; 4:1-10) 33 6 states, USA 1995-1996 Cohort, nested case-control (AARP study) (Schatzkin et al., 2001) 34 Multicentric, Brazil 2016-2020 Case-control, hospital-based None available yet 35 Lithuania 2005-2017 Case-control, genetic data only (Dargiene et al, 2018)

The role of specific food groups and diet variety on the risk of oral and pharyngeal cancer has been considered using data from a case-control study conducted between 1992 and 1997 in the Swiss Canton of Vaud. Cases were 156 patients (126 males, 30 females) aged under 75 (median age 56) years with incident, histologically confirmed cancer of the oral cavity and pharynx, and controls were 284 subjects (246 males, 38 females, median age 57 years), admitted to the same university hospital for a wide spectrum of acute, non-neoplastic conditions unrelated to tobacco and alcohol consumption or to long-term modification of diet. After allowance for education, alcohol, tobacco and total energy intake, significant trends of increasing risk with more frequent intake emerged for eggs (OR = 2.3 for the highest tertile), red meat (OR = 2.1) and pork and processed meat (OR = 3.2). Inverse trends in risk were observed for milk (OR = 0.4 for the highest tertile), fish (OR = 0.5), raw vegetables (OR = 0.3), cooked vegetables (OR = 0.1), citrus fruit (OR = 0.4) and other fruits (OR = 0.2). The addition of a serving per day of fruit or vegetables was associated with an about 50% reduction in oral cancer risk. The most favourable diet for oral cancer risk is therefore given by infrequent consumption of red and processed meat and eggs and, most of all, frequent vegetable and fruit intake. Diet diversity was inversely related to oral and pharyngeal cancer: ORs were 0.35 for the highest tertile of total diversity, 0.24 for vegetable and 0.34 for fruit diversity. In terms of attributable risk, high meat intake accounted for 49% of oral and pharyngeal cancers in this population, low vegetable intake for 65% and low fruit intake for 54%. Int. J. Cancer 77:705–709, 1998. © 1998 Wiley-Liss, Inc.

This study considers the prevalence of early bleeding in a series of 173 cases of endometrial cancer, with particular reference to the lag time between the onset of symptoms and diagnosis. The length of this interval is examined in the light of patients' and tumor characteristics. Findings show a general delay in endometrial cancer diagnosis in the population studied. In addition there was a significant trend towards worsening of the tumor stage, depth of myometrial invasion and histological differentiation with increasing delay, thus underlining the need for more care in detection of endometrial cancer.

In view of the persisting uncertainty concerning possible mechanisms by which high vegetable and fruit intake decreases cancer risk, foods with divergent values for potentially important micronutrients are a priority for investigation. Tomatoes are low in beta-carotene, but high in lycopene, an active antioxidative agent. In order to assess the effect of tomatoes on risk of cancers of the digestive tract, data were analyzed from an integrated series of case-control studies conducted between 1985 and 1991 in northern Italy, where tomato intake is high but, also, heterogeneous. The overall dataset included the following histologically confirmed cancer cases: oral cavity and pharynx, 314; esophagus, 85; stomach, 723; colon, 955; and rectum, 629; and a total of 2,879 controls admitted to hospital for acute non-neoplastic or non-digestive conditions, unrelated to long-term dietary modifications. Multivariate odds ratios (OR) and 95% confidence interval (CI) for subsequent quartiles of intake of raw tomatoes were derived, after allowance for age, sex, study center, education, smoking and drinking level, and tertile of total caloric intake. There was a consistent pattern of protection for all sites (OR in the upper quartile ranging between 0.4 and 0.7), most notably for gastrointestinal neoplasms. All trends in risk were highly significant. The beneficial effect of raw tomatoes in this population may be partly due to the fact that they constitute perhaps the most specific feature of the Mediterranean diet. However, if it is true that tomatoes protect against digestive-tract cancers, this is of interest from both a scientific and a public health viewpoint.

Studyobjective - The studyaimedto investigate the relationship between yearssincestopping smoking andtherisk ofacutemyocardial infarction. Design-Thiswasahospital based, multicentre, case-control studyconducted in ItalybetweenSeptember1988andJune 1989withintheframework oftheGISSI-2 clinical trial. Setting -Over80coronarycareunitsin various Italian regions participated. Subjects -A total of916incident casesof acutemyocardial infarction, belowage 75years, andwithnohistory ofischaemic heartdisease, and1106control subjects admitted tothesamehospitals foracute, non-neoplastic, cardiovascular or cerebrovascular conditions thatwere not knownorsuspected toberelated tocigarettesmokingtookpartinthestudy. Main outcomemeasuresandresults Measureswererelative risk(RR)estimatesof acutemyocardialinfarction according to thetimesincestopping smokingand adjusted foridentified potential confounding factors. Comparedwithneversmokers, themultivariateRRswere1-6(95%confidence interval(CI)0-8,3 2)forsubjects who had givenupsmokingforoneyear;1-4(95% CI0-9,2-1) forthosewhohadstopped for twotofiveyears; 1-2(95%CI0-7,2-1) for sixto10years; and11(95%CI0-8,1-8) for thosewho hadnotsmokedforover10 years.The estimated RR forcurrent smokerswas 2-9(95%CI22,3-9). The risks ofquitters werehigherforheavier smokersandthosebelowage50years, whilenodifference emergedinrelation to theduration ofsmoking, sex,andother riskfactors formyocardial infarction. Conclusions -Theseresults indicate that thereisalready asubstantial dropinthe riskofacutemyocardial infarction one yearafterstopping. The riskin ex

Genetic complementation experiments have indicated that both a maternal and a paternal copy of the distal region of mouse chromosome 7 are essential for normal development [1]. This suggested the presence of genes whose expression is dependent on the gamete of origin in this chromosomal region. Two such imprinted genes, namely insulin-like growth factor II ( Igf 2) and H 19, have been identified so far [2, 3]. The first encodes a peptide with mitotic activity towards several cell types, that contributes significantly to prenatal growth of mammals, whereas the second has, as yet, no defined role and seems not to encode any protein, but works as RNA. ( Igf 2) and H19 are located 90 kb apart, have similar expression patterns during development and are reciprocally imprinted, since the maternal Igf 2 and the paternal H19 alleles are inactive in most fetal tissues [4, 5].

The relationship between cancer risk and frequency of consumption of green vegetables and fruit has been analyzed using data from an integrated series of case-control studies conducted in northern Italy between 1983 and 1990. The overall dataset included the following histologically confirmed cancers: oral cavity and pharynx, 119; oesophagus, 294; stomach, 564; colon, 673; rectum, 406; liver, 258; gall-bladder, 41; pancreas, 303; larynx, 149; breast, 2,860; endometrium, 567; ovary, 742; prostate, 107; bladder, 365; kidney, 147; thyroid, 120; Hodgkin's disease, 72; non-Hodgkin lymphomas, 173; myelomas, 117; and a total of 6,147 controls admitted to hospital for acute non-neoplastic conditions, unrelated to long-term dietary modifications. Multivariate relative risks (RR) for subsequent tertiles of vegetable and fruit consumption were derived after allowance for age, sex, area of residence, education and smoking. For vegetables, there was a consistent pattern of protection for all epithelial cancers, with RRs in the upper tertile ranging from 0.2 for oesophagus, liver and larynx to 0.7 for breast. All the trends in risk were in the same direction and significant for all carcinomas except gall-bladder. In contrast, no protection was afforded by high vegetable consumption against non-epithelial lymphoid neoplasms. With reference to fruit, strong inverse relationships were observed for cancers of the upper digestive and respiratory tract, with RRs in the upper tertile between 0.2 and 0.3 for oral cavity and pharynx, oesophagus and larynx relative to the lowest tertile. The lower the location of the tumour in the digestive tract, the weaker appeared to be the protection afforded. Significant inverse relationships were observed for liver, pancreas, prostate and urinary sites, but not for rectum, breast and female genital cancers or thyroid. No relationship emerged for lymphomas and myelomas. Even in the absence of a clear biological interpretation, the consistency and strength of the patterns observed indicate that, in this population, frequent green vegetable intake is associated with a substantial reduction of risk for several common epithelial cancers, and that fruit intake has a favourable effect, especially on upper digestive cancers and, probably, also on urinary tract neoplasms.

The ultimate aim is to foster PC research in Europe and to coordinate this effort with other international initiatives to reduce disease mortality.