Publications

Background: The prevalence of Helicobacter pylori-negative gastric cancer (HpNGC) can be as low as 1%, when infection is assessed using more sensitive tests or considering the presence of gastric atrophy. HpNGC may share a high-risk profile contributing to the occurrence of cancer in the absence of infection. We estimated the proportion of HpNGC, using different criteria to define infection status, and compared HpNGC and positive cases regarding gastric cancer risk factors. Methods: Cases from 12 studies from the Stomach cancer Pooling (StoP) Project providing data on H. pylori infection status determined by serologic test were included. HpNGC was reclassified as positive (eight studies) when cases presented CagA markers (four studies), gastric atrophy (six studies), or advanced stage at diagnosis (three studies), and were compared with positive cases. A two-stage approach (random-effects models) was used to pool study-specific prevalence and adjusted odds ratios (OR). Results: Among non-cardia cases, the pooled prevalence of HpNGC was 22.4% (n = 166/853) and decreased to 7.0% (n = 55) when considering CagA status; estimates for all criteria were 21.8% (n = 276/1, 325) and 6.6% (n = 97), respectively. HpNGC had a family history of gastric cancer more often [OR = 2.18; 95% confidence interval (CI), 1.03-4.61] and were current smokers (OR = 2.16; 95% CI, 0.52-9.02). Conclusion: This study found a low prevalence of HpNGC, who are more likely to have a family history of gastric cancer in first-degree relatives. Impact: Our results support that H. pylori infection is present in most non-cardia gastric cancers, and suggest that HpNGC may have distinct patterns of exposure to other risk factors.

The objective of this study is to investigate the effect of menstrual and reproductive variables, breastfeeding, exogenous hormones, and gynecological conditions on endometrial cancer risk. We conducted a case-control study in Italy, including 454 women with endometrial cancer and 908 hospital controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate logistic regression models. Endometrial cancer risk was inversely associated with age at menarche (OR = 0.7, 95% CI = 0.5-1.0, for > or =14 vs. <12 years), and directly associated with age at menopause (OR = 1.8, 95% CI = 1.1-2.7, for > or =55 vs. <50 years) and years of menstruation (OR = 2.4, 95% CI = 1.7-3.4, for highest vs. lowest tertile). Multiparity strongly reduced the risk among women under 60 years of age (OR = 0.3, 95% CI = 0.2-0.6, for > or =3 deliveries vs. <2). Oral contraceptive use conferred a 40% reduced risk (95% CI = 0.4-1.0), irrespective of time since cessation. Although based on small numbers, women with a history of treated infertility (OR = 2.7, 95% CI = 1.1-6.4) or endometriosis (OR = 4.0, 95% CI = 1.0-15.5) were at increased risks. No significant associations with endometrial cancer risk emerged for age at first/last birth, breastfeeding, menopausal status, hormone replacement therapy, and history of uterine fibromyomas or polycystic ovary. In conclusion, this study confirms the importance of multiparity, years of menstruation, and oral contraceptive use in endometrial cancer etiology, thus contributing to identify women at elevated risk of such neoplasm.

To elucidate the role of dietary habits, a study was carried out in 1992-1997 in the province of Pordenone in Northeastern Italy, and those of Rome and Latina in central Italy. Cases were 512 men and 86 women with cancer of the oral cavity and pharynx (lip, salivary glands and nasopharynx excluded) and controls were 1008 men and 483 women who had been admitted to local hospitals for a broad range of acute non-neoplastic conditions. The validated dietary section of the questionnaire included 78 foods or recipes and ten questions on fat intake patterns. After allowance for education, smoking, alcohol and total energy intake, significant trends of increasing risk with increasing intake emerged for soups, eggs, processed meats, cakes and desserts, and butter. Risk was approximately halved in the highest compared to the lowest intake quintile for coffee and tea, white bread, poultry, fish, raw and cooked vegetables, citrus fruit, and olive oil. The inverse association with oils, especially olive oil, was only slightly attenuated by allowance for vegetable intake. Thus, frequent consumption of vegetables, citrus fruit, fish and vegetable oils were the major features of a low-risk diet for cancer of the oral cavity and pharynx.

Preclinical findings suggest that aspirin might inhibit pancreatic carcinogenesis, but epidemiological data are scanty and controversial. The role of aspirin use in pancreatic cancer is further analyzed in a multicentric hospital-based case-control study conducted in Italy between 1991 and 2008. Cases were 308 patients with incident pancreatic cancer and controls were 477 patients admitted to the same hospitals as cases for acute conditions, not related to risk factors for pancreatic cancer. A total of 22 cases (7%) and 37 controls (8%) reported regular aspirin use, with a corresponding adjusted odds ratio (OR) of 0.87 [95% confidence interval (CI): 0.47-1.61]. A slight protection, although not significant, was observed for duration of use > or =5 years (OR=0.53; 95% CI: 0.21-1.33) and for time since first use > or =10 years (OR=0.69; 95% CI: 0.25-1.93). The risk of pancreatic cancer was significantly below unity for current users of > or =5 years (OR=0.23; 95% CI: 0.06-0.90), but the risk was based on three cases and 16 controls only. We observed no association between regular aspirin use and pancreatic cancer risk, although our results suggested a possible protective effect for long-term current users.

Nutritional status is known to alter immune function, a suspected risk factor for non-Hodgkin lymphoma (NHL). To investigate whether long-term over, or under, nutrition is associated with NHL, self-reported anthropometric data on weight and height from over 10,000 cases of NHL and 16,000 controls were pooled across 18 case-control studies identified through the International Lymphoma Epidemiology Consortium. Study-specific odds ratios (OR) were estimated using logistic regression and combined using a random-effects model. Severe obesity, defined as BMI of 40 kg m(-2) or more, was not associated with NHL overall (pooled OR = 1.00, 95% confidence interval (CI) 0.70-1.41) or the majority of NHL subtypes. An excess was however observed for diffuse large B-cell lymphoma (pooled OR = 1.80, 95% CI 1.24-2.62), although not all study-specific ORs were raised. Among the overweight (BMI 25-29.9 kg m(-2)) and obese (BMI 30-39.9 kg m(-2)), associations were elevated in some studies and decreased in others, while no association was observed among the underweight (BMI < 18.5 kg m(-2)). There was little suggestion of increasing ORs for NHL or its subtypes with every 5 kg m(-2) rise in BMI above 18.5 kg m(-2). BMI components height and weight were also examined, and the tallest men, but not women, were at marginally increased risk (pooled OR = 1.19, 95% CI 1.06-1.34). In summary, whilst we conclude that there is no evidence to support the hypothesis that obesity is a determinant of all types of NHL combined, the association between severe obesity and diffuse large B-cell lymphoma may warrant further investigation.

Circulating branched-chain amino acids (BCAA), a subgroup of the nine essential amino acids, has been associated with pancreatic cancer risk. The aim of this study is to estimate the relation between BCAA intake from diet and pancreatic cancer risk. We analysed data from a multicentric Italian case-control study, including 326 pancreatic cancer cases and 652 controls, matched to cases by study centre, sex and age. A validated FFQ was used to collect the participants' usual diet before cancer diagnosis (or hospital admission for controls) and to compute dietary intakes of various nutrients, including BCAA. OR and the corresponding CI were computed through logistic regression models conditioned on the matching variables and adjusted for major confounding factors, including total energy intake. We found a positive association between BCAA intake and pancreatic cancer risk (OR for the third quartile = 1·88, 95 % CI = 1·08, 3·26; OR for the fourth quartile = 2·17, 95 % CI = 1·17, 4·06), with a significant trend in risk. The association persisted after excluding subjects with diabetes and family history of pancreatic cancer and across strata of selected covariates. These data support and quantify the association between dietary BCAA and pancreatic cancer, previously suggested by studies on circulating BCAA.

Abstract High-grade B-cell lymphomas (HGBCL) encompass a heterogeneous group of aggressive B-cell malignancies. The most common genetically defined subtype, HGBCL with BCL2 and MYC rearrangements (HGBCL-DH-BCL2), is characterized by hallmark chromosomal translocations and poor prognosis, even in the era of improved chemo-immunotherapy, CAR-T cells, and antibody-drug conjugates1-3. Progress in this field is hindered by the lack of robust preclinical models that accurately capture the complex biology of the disease. Our recent work has reported recurrent silencing of the B cell receptor (BCR) in primary cases of HGBCL-DH-BCL2⁴. This phenotype is associated with gene expression programs characteristic of germinal center (GC) dark-zone (DZ) B cells4,5. Histological analyses have also established that HGBCL-DH-BCL2 (particularly those silencing the BCR), display an immune-cold microenvironment that closely resembles that of the GC dark zone5,6. Mutational analyses in HGBCL-DH-BCL2 have revealed recurrent gain-of-function mutations in the GC dark-zone determinant FOXO15. In addition, HGBCL-DH-BCL2 frequently inactivate the TP53 axis and share with Burkitt lymphoma expression of degron-resistant forms of CCND3 (i.e., CCND3T283A)5. HGBCL-DH-BCL2 is often preceded by follicular lymphoma (FL), characterized by BCL2 deregulation as its molecular hallmark. Finally, constitutive expression of an often mutant form of the MYC protein (i.e. MYCT58A) in a BCL2-rearranged FL or t(14;18)+ GC DZ B cell precursor represents the ultimate oncogenic event driving transformation to HGBCL-DH-BCL2. To model this transformation trajectory, we adapted a previously established retroviral transduction system7 for genetic engineering of primary human GC B cells. We constructed retroviral vectors encoding wild-type or mutant forms of lymphoma-relevant genes linked to fluorescent or surface markers for single-cell tracking. Primary GC B cells purified from human tonsils were first transduced with a four-gene cocktail (Oncomix-1) expressing BCL2, BCL6, FOXO1M1L, and dominant-negative TP53 (TP53DD). These genes cooperatively promoted survival and proliferation for &amp;gt; 4 weeks in vitro on CD40L/IL-21-expressing YK6 feeder cells. However, engineered cells remained dependent on exogenous stimulation and failed to form tumors in immunocompromised mice. To mimic the MYC oncogenic event driving HGBCL-DH-BCL2 onset, Oncomix-1-infected cells were superinfected with a second retroviral cocktail (Oncomix-2) expressing mutant MYCT58A and CCND3T283A. This step conferred mitogen independence, rapid proliferation in 2D culture, and tumor formation in NSG xenografts, hallmarks of transformation. In vivo tumors showed histological features of aggressive GCB-like lymphomas. Given that most HGBCL-DH-BCL2 silence their BCR, we sought to reproduce this phenotype. We engineered Oncomix-1-infected cells with an alternative Step-2 retroviral cocktail (Oncomix-3) combining MYCT58A and CCND3T283A, to wild-type KLHL6, a GC DZ-enriched BTB-domain adaptor that targets the BCR subunit CD79B for proteasomal degradation8,9. Deregulated KLHL6 expression supported the emergence of a rapidly expanding, BCR-negative GC immortalized B cell population. These cells showed a GC DZ-like immunophenotype and feeder-independent growth, closely mimicking the phenotype of BCR-silenced HGBCL-DH-BCL2. In summary, we established a stepwise viral transduction protocol to model the progressive transformation of human GC B cells into DZ–like HGBCL, driven by consecutive deregulation of the BCL2 and MYC oncoproteins. This model recapitulates key transcriptional, immunophenotypic, and oncogenic features of HGBCL-DH-BCL2 offering a versatile tool for mechanistic dissection (including immune evasion) and pharmacologic interrogation. References Melani C et al. N Engl J Med. 2024. doi:10.1056/NEJMoa2401532. Phina-Ziebin X et al. Blood Adv. 2025. doi:10.1182/bloodadvances.2024014732 Schneider M et al. Clin Lymphoma Myeloma Leuk. 2025. doi: 10.1016/j.clml.2024.08.010. Hilton LK et al. Blood. 2024. doi: 10.1182/blood.2024024251 Varano G et al. Blood Cancer Discov. 2025. doi: 10.1158/2643-3230.BCD-25-0099 Cancila V et al. J Clin Invest. 2025.doi: 10.1172/JCI187371 Caeser R et al. Nat Commun. 2019. Doi: 10.1038/s41467-019-12494-x Meriranta L et al. Blood Cancer Discov. 2024. doi: 10.1158/2643-3230.BCD-23-0182 Corcoran SR et al. Cancer Discov. 2024. doi: 10.1158/2159-8290.CD-23-0802

Boyle, P. PhD*; Zheng, T. MD*†; Macfarlane, G. J. MD‡§; McGinn, R. MD*; Maisonneuve, P. Ing*; LaVecchia, C. MD¶; Scully, C. MD§ Author Information

To evaluate the association between coffee, decaffeinated coffee, and tea consumption and pancreatic cancer risk in a pooled analysis of two Italian case-control studies, between 1983 and 2008, we conducted two case-control studies in Northern Italy, including a total of 688 pancreatic cancer cases and 2204 hospital controls with acute, non-neoplastic diseases. We computed multivariate odds ratios (ORs) and 95% confidence intervals (CIs) for coffee drinking (mostly espresso and mocha), adjusting for age, sex, center, year of interview, education, body mass index, tobacco smoking, alcohol drinking, and diabetes. Compared with coffee nondrinkers, the multivariate OR for coffee drinkers was 1.34 (95% CI: 1.01-1.77). However, there was no trend in risk with respect to dose and duration. The OR for an increment of one cup per day was 1.05 (95% CI: 0.98-1.11). There was no heterogeneity in strata of age, sex, and other covariates, including tobacco smoking. No association emerged for decaffeinated coffee (for drinkers the OR was 0.87, 95% CI: 0.60-1.26, compared with decaffeinated coffee nondrinkers) or tea (for tea drinkers the OR was 0.92, 95% CI: 0.75-1.14). The lack of relationship with dose and duration weighs against a causal association between coffee and pancreatic cancer, which is in agreement with most evidence on the issue.