The decrease in stomach cancer mortality was not because of specific interventions, and is likely that different countries follow a similar model of variation. Here, we aimed to identify model-based patterns in the time trends of stomach cancer mortality worldwide. Stomach cancer mortality rates were retrieved for 62 countries from the WHO mortality database. Sex-specific mixed models were used to describe time trends in age-standardized rates between 1980 and 2010 (age group 35-74 years; World standard population). Three patterns, similar for men and women, were identified through model-based clustering. Pattern 1 presented the highest mortality rates in 1980 (median: men, 81.5/100 000; women, 34.4/100 000) and pattern 3 the lowest ones (median: men, 24.4/100 000; women, 12.4/100 000). The decrease in mortality rates was greater in 1980-1995 than during 1996-2010. Assuming that the patterns characterized by the highest rates precede temporally those with lower mortality, the overlap of model predictions supports a 20-year lag between adjacent patterns. We propose a model for the variation in stomach cancer mortality with three stages that develop sequentially through a period of ∼70 years. The countries with the lowest mortality had the highest proportional decrease in mortality rates.
Abstract High-grade B cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) represent an infrequent, life-threatening clinical entity with poor prognosis. Recent advances, including novel chemotherapy regimens1, antibody-drug conjugates2, and CAR-T cell therapies3, have shown promise, yet durable disease-free survival remains elusive for most patients. A better understanding of the mechanisms underlying HGBCL-DH-BCL2 onset is key to the development of personalized therapies or integration of molecularly targeted interventions into existing regimens. Another potentially life-saving strategy involves anticipating HGBCL-DH-BCL2 emergence by studying the biology of follicular lymphoma (FL) that often precedes transformation. Identifying cell-intrinsic and/or microenvironment-associated molecular and spatial features specifically linked to FL evolution into HGBCL-DH-BCL2 may enable discovery of clinically relevant biomarkers predictive of transformation risk and alert on the presence of putative HGBCL precursor cells already present within FL. We have recently shown that HGBCL-DH-BCL2 frequently exhibit B cell receptor (BCR) silencing4. This phenotype is often accompanied by re-expression of the RAG1/2 recombinases, contributing to antigen receptor revision and irreversible BCR extinction4. Notably, we have provided evidence for RAG activity to be causally linked to HGBCL-DH-BCL2 outgrowth via IGL::MYC, t(8;22) translocations, postulating recombinase reactivation in the precursor cell as a key pathogenetic event4. To identify such precursor cells, we analyzed 10 FL cases for which RAG1/2 expression had already been measured in their metachronous HGBCL-DH-BCL2 counterpart4. FL specimens were paired with six RAG-positive HGBCL-DH-BCL2cases, while the remaining four paired with RAG-negative ones. On the same FFPE section, we combined RNA scope to detect RAG1/2 transcripts with DNA FISH for t(14;18) to spatially map RAG-expressing (pre)malignant B cells within FL. Also, RAG1/2 mRNA detection was matched with immunohistochemistry for LMO2 to assess the relation of RAG+ cells to the germinal center reaction. In a subset of cases, we compared Immunoglobulin (IG) light chain isotype usage between metachronous lymphomas to assess ongoing RAG-dependent receptor editing. RAG1/2 transcripts were detected in a distinct fraction of LMO2+BCL2+ t(14;18)+ cells in five of six (83%) FL cases anticipating RAG-positive HGBCL-DH-BCL2.An additional FL case displayed a sizeable pool of RAG1/2-expressing cells, despite its transformed counterpart failed to display detectable recombinases expression in the second bioptic sample. Three of the four RAG-negative HGBCL-DH-BCL2 cases mirrored this phenotype in their respective FL precursors. Building on our recent work showing that RAG-positive HGBCL-DH-BCL2 cases can exhibit IG light chain isotype inclusion4, we show that in two such cases, co-expression of IGK and IGL light chains is already present in the preceding FL, indicating early onset of antigen receptor revision. Altogether, in situ studies of paired FL and HGBCL-DH-BCL2 specimens identified for the first time a distinct subset of RAG-expressing, t(14;18)+ LMO2+ germinal center-like B cells in FL specimens that later progressed to recombinase-positive HGBCL-DH-BCL2. Given the causal link between RAG expression and IGL::MYC rearrangements caused by aberrant VJ recombination in a subset of HGBCL-DH-BCL24, we propose that RAG-expressing cells in FL represent strong candidates for HGBCL-DH-BCL2 precursor cells. References Melani C, Lakhotia R, Pittaluga S, et al. Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma. N Engl J Med. 2024;390(23):2143-2155. Schneider M, Nasta SD, Barta SK, et al. Analysis of Histologic, Immunohistochemical and Genomic Features of Large B Cell Lymphoma Tumors May Predict Response to Polatuzumab Vedotin Based Therapy in Patients With Relapsed/Refractory Disease. Clin Lymphoma Myeloma Leuk. 2025;25(1):45-51. Phina-Ziebin X, Bachy E, Gros FX, et al. Outcome of high-grade B-cell lymphoma compared with other large B-cell lymphoma after CAR-T rescue: a DESCAR-T LYSA study. Blood Adv. 2025;9(10):2500-2510. Varano G, Lonardi S, Sindaco P, et al. B cell receptor silencing reveals origin and dependencies of high-grade B cell lymphomas with MYC and BCL2 rearrangements. Blood Cancer Discov. 2025.
The Dietary Approaches to Stop Hypertension (DASH) diet is an effective measure in the prevention and treatment of CVD. We evaluated recent trends in socio-economic differences in the DASH score in the UK population, using education, occupation and income as proxies of socio-economic position (SEP). We analysed data on 6416 subjects aged 18 years and older collected in the National Diet and Nutrition Survey (2008-2016). The DASH score was calculated using sex-specific quintiles of DASH items. Multiple linear regression and quantile regression models were used to evaluate the trend in DASH score according to SEP. The mean DASH score was 24 (sd 5). The estimated mean difference between people with no qualification and those having the highest level of education was -3·61 (95 % CI -4·00, -3·22) points. The mean difference between subjects engaged in routine occupations and those engaged in high managerial and professional occupations was -3·41 (95 % CI -3·89, -2·93) points and for those in the first fifth and last fifth of the household income distribution was -2·71 (95 % CI -3·15, -2·28) points. DASH score improved over time, and no significant differences in the trend were observed across SEP. The widest socio-economic differences emerged for consumption of fruit, vegetables, whole grains, nuts, seeds and legumes. Despite an overall increase in the DASH score, a persisting SEP gap was observed. This is an important limiting factor in reducing the high socio-economic inequality in CVD observed in the UK.
Available statistics on smoking, alcohol, food supply, reproductive history, and other lifestyle habits from the U.S. and Italy were compared and related to mortality rates of common neoplasms over the period 1955 to 1980. Per capita cigarette consumption has declined in the U.S. since the early 1960s but continues to rise in Italy, chiefly due to the recent increase in cigarette smoking among Italian women. Alcohol consumption has increased in both countries, being persistently about 40% higher in Italy. Changes were relatively limited in the American diet, but substantial for the Italian one which had particularly marked increases in meat, milk, and fat consumption. Fertility rates have declined in both countries but more sharply in the U.S. These lifestyle changes were reflected by distinctly divergent trends in cancer mortality rates between the two countries. In Italian males, mortality rates of urinary bladder cancer and alcohol-related neoplasms of the aerodigestive tract (oral cavity, larynx, and esophagus) increased in a similar manner and were persistently elevated relative to American males. Similarly, Italian lung cancer rates, while starting from lower values, rose steadily to overtake American rates in the younger and middle age groups of both sexes, and neoplasms of the intestines, breast, and ovary, starting from considerably lower values, tended to approach the American rates over the 25-year period considered. Within Italy, mortality rates of most common neoplasms were substantially elevated in the North of the country relative to the South, thereby paralleling the distinct North to South gradient in socioeconomics, diet, and affluent lifestyle which exists in the country. In our opinion, most of these trends are real, and their explanation should be sought, partly or largely, in the changes in tobacco and alcohol use, and the reproductive and dietary patterns described. The evidence presented underlies the importance of this kind of exercise to formulate and test etiological hypotheses of human diseases, which may be overlooked in studies based on populations with more homogeneous lifestyle habits or environmental exposures.
The relationship between frequency of consumption of a selected number of indicator foods and oral and oropharyngeal cancer risk was analysed in a case-control study conducted in Northern Italy on 105 cases of oral and pharyngeal cancer and 1169 controls in hospital for acute, non-neoplastic or digestive diseases. Besides significant and strong direct associations with tobacco (relative risk, RR = 11.0 for current versus never smokers) and alcohol (RR = 5.8 for upper versus lower consumption tertile), consumption of six food items (milk, meat, cheese, carrots, green vegetables and fruit) were inversely and significantly related to oral and pharyngeal cancer risk. The strongest protection was apparently related to frequent fruit consumption, with RRs of 0.8 and 0.2 in the two highest tertiles. Allowance for major potential confounding factors, including tobacco, alcohol and social class indicators explained only part of the dietary correlates observed. The two items remaining significant after multivariate analysis were fruit (RR = 0.3 for the upper tertile) and alcohol (RR = 3.8 for the upper tertile). The associations observed may simply reflect a generally poorer nutritional status in the cases, although the observation that fruit consumption appears to be a particularly important protective factor against oropharyngeal cancer is of potential interest, in terms of aetiological clues and preventive implications.
The relationship between reproductive variables (parity, age at first birth, number of induced and spontaneous abortions) and cancer risk has been analysed using data from an integrated series of case-control studies conducted in northern Italy between 1983 and 1992. The overall data-set included women below age 75 with histologically confirmed cancers of the following sites: oesophagus, 58; stomach, 280; colon, 405; rectum, 210; liver, 82; gall-bladder, 29; pancreas, 129; breast, 3,415; cervix, 742; endometrium, 725; ovary, 953; bladder, 68; kidney, 56; thyroid, 180; lymphomas, 80; myelomas, 57; and a total of 5,619 controls admitted to hospital for acute non-neoplastic, non-gynaecological, non-hormone-related conditions. Multivariate odds ratios, as estimators of relative risks (RR), were obtained after allowance for age, education, use of oral contraceptives and oestrogen replacement treatments, plus various reproductive factors. Direct significant trends with parity were observed for cancer of the liver (RR for women with > or = 4 births vs. nulliparae = 3.3) and cervix uteri (RR = 4.1). The risk of gall-bladder cancer was also elevated for multiparae (RR = 1.9). No significant inverse trend in risk emerged. However, the RRs in multiparae were significantly below unity for breast (RR = 0.8), endometrium (RR = 0.7), and ovary (RR = 0.8). With reference to age at first birth, a significant trend in risk was observed for breast cancer (RR = 1.4 for 25 to 29 and 1.5 for > or = 30 vs. < 25 years). In contrast, the risk of cervical cancer was inversely related to age at first birth. For spontaneous abortions, the only significant inverse trend was for ovarian cancer (RR = 0.7 for > or = 2 vs. 0 abortions), but also the point estimate for endometrial cancer in women with > or = 2 abortions was below unity. For induced abortions, there was a strong inverse trend in risk for endometrial cancer (RR = 0.5), and the RRs were below unity also for colon and breast cancer. In contrast, cervical cancer was directly associated with the number of spontaneous abortions. Although the underlying aetiological interpretations are different for various cancer sites, this study provides, in a large and uniform data-set, quantitative information on the long-term impact of reproductive factors on cancer risk.
