Carla Vindigni

Haematopoietic cancer and medical history: a multicentre case control study

BACKGROUND Viruses (such as Epstein-Barr virus) and pathological conditions (mainly involving immunosuppression) have been shown to increase the risk of haematolymphopoietic malignancies. Other associations (diabetes, tonsillectomy, autoimmune diseases) have been inconsistently reported. METHODS The association between different haematolymphopoietic malignancies (lymphomas, myelomas and leukaemias) and the previous medical history has been studied in a population-based case-control investigation conducted in Italy, based on face to face interviews to 2669 cases and 1718 population controls (refusal rates 10% and 19%, respectively). Controls were a random sample of the general population. RESULTS Previous findings were confirmed concerning the association between non-Hodgkins lymphoma (NHL) and lupus erythematosus (odds ratio, OR=8.4; 95% CI 1.6, 45), tuberculosis (OR=1.6; 1.05, 2.5) and hepatitis (1.8; 1.4, 2.3). An association was found also between NHL and maternal (OR=2.8; 1.1, 6.9) or paternal tuberculosis (OR=1.7; 0.7, 3.9). Odds ratios of 4.0 (1.4, 11.8) and 4.4 (1.1, 6.6) were detected for the association between NHL and Hodgkins disease, respectively, and previous infectious mononucleosis, but recall bias cannot be ruled out. No association was found with diabetes, tonsillectomy and adenoidectomy. An association with malaria at young age and “low grade” lymphatic malignancies is suggested. One interesting finding was the observation of four cases of poliomyelitis among NHL patients, one among Hodgkins disease and one among myeloid leukaemia patients, compared with none among the controls (Fishers exact test for NHL and Hodgkins disease, p= 0.03, one tail). CONCLUSIONS Some of these findings are confirmatory of previous evidence. Other observations, such as the putative role of the polio virus and of malaria are new. A unifying theory on the mechanisms by which previous medical history may increase the risk of haematolymphopoietic malignancies is still lacking.

Occupational, environmental, and life-style factors associated with the risk of hematolymphopoietic malignancies in women

BACKGROUND The etiology of lymphomas, leukemias, and multiple myeloma is still largely unknown. The known risk factors (ionizing radiation, solvent exposure, pesticide exposure, immunosuppression) explain only a small proportion of the cases that occur. METHODS We conducted a multicenter population-based case-control study on hematolymphopoietic malignancies in Italy and interviewed 2,011 women (1,183 cases and 828 controls). RESULTS There was a suggestion of a positive association between smoking and the risk of non-Hodgkins lymphoma + chronic lymphocytic leukemia. A slight increased risk of leukemias was observed among women using permanent hair dye. Housewives were at increased risk for leukemia and multiple myeloma. The risk of non-Hodgkins lymphomas + chronic lymphocytic leukemia, leukemias, multiple myeloma, and Hodgkins disease increased among women employed as hairdressers and textile workers. Teachers were at increased risk for non-Hodgkins lymphomas + chronic lymphocytic leukemia, leukemias, and Hodgkins disease. CONCLUSIONS These results confirm previous associations and may provide additional clues to some determinants of hematolymphopoietic malignancies in women.

A case-control study of cancers of the gastric cardia in Italy

In a case-control study of gastric cancer (GC) in high-risk and low-risk areas in Italy, 923 GCs were reviewed by one pathologist and classified according to anatomic site. There were 68 (7.4%) cancers occurring in the gastric cardia. Compared to other GCs, cardia cancer tended to occur more often in males (sex ratio 2.8 vs 1.7) and as intestinal or unclassified histologic types. Nutritional factors for cardia tumours resembled those of other GCs, showing inverse associations with the consumption of raw vegetables, citrus and other fresh fruit, and ascorbic acid, and positive associations with the intake of traditional soups and meat, protein and cholesterol, and preference for salty foods. Cigarette smoking and wine consumption were unrelated to cardia cancer risk, and there was only a weak association with total alcohol intake. Cardia tumours showed a greater familial occurrence of GC than did other sites, with a 7-fold increase in risk for those reporting two first-degree relatives with GC. The authors discuss these findings in view of the rising incidence of adenocarcinomas of the cardia and lower oesophagus that has been reported in some western countries.

Deciphering the underlying genetic and epigenetic events leading to gastric carcinogenesis

Gastric cancer is a common aggressive malignancy. Although its incidence shows considerable variation among different countries, gastric cancer is still a major health problem worldwide. The causes of stomach cancer are not completely understood. What is clear is that gastric cancer is a multi‐stage process involving genetic and epigenetic factors. This review is an in‐depth study of the known genetic and epigenetic processes in the development of this tumor, and delineates possible approaches in gene and epigenetic therapy. J. Cell. Physiol. 211: 287–295, 2007.

Smoking and hematolymphopoietic malignancies

Objective: Tobacco use is the most prominent cause of respiratory cancers. Little is known, however, about the influence of smoking on hematolymphopoietic malignancies. To evaluate this relation, a population-based case–control study was carried out in 12 areas of Italy. Methods: Detailed interviews on tobacco smoking habits were administered to 1450 non-Hodgkins lymphoma (NHL), 365 Hodgkins disease (HD), 270 multiple myeloma (MM), and 649 leukemia (LEU) patients occurring from 1990 to 1993, and 1779 population controls. Results: We found a slightly increased risk for NHL in smokers (odds ratio 1.2, 95% confidence interval 1.0–1.4 for ever smokers), but a consistent positive association was shown only for follicular NHL. In this subtype, a significant excess risk was observed for ever versus never smokers, after adjustment for gender, age, geographic residence, education, and respondent (OR = 1.8, 95%, CI 1.3–2.7), with a positive exposure–response gradient for smoking duration (p<0.01). The risk for follicular NHL was significantly elevated only among women, with ever smokers showing OR = 2.3 (CI 1.4–3.8), while for men we found OR = 1.3 (CI 0.69–2.3). No major differences were shown according to age. Female subjects also showed significant positive exposure–response trends for duration. Conclusion: Cigarette smoking could be a risk factor for follicular NHL among women. For HD, MM, or LEU, no clear association was observed.

A multicenter case-control study in Italy on hematolymphopoietic neoplasms and occupation

We conducted a population-based, case-control study on hematolymphopoietic malignancies in 12 areas in Italy to investigate associations between different hematolymphopoietic malignancies and exposure to solvents and pesticides. We collected all incident cases 20–74 years of age from 12 areas, with a combined population of approximately 7 million residents. The control group was formed by a random sample of the study population. Data presented in this paper refer to 2,737 interviewed cases of 3,357 eligible cases and to 1,779 of 2,391 eligible controls. We analyzed risks associated with occupation using job-title information to evaluate disease pattern according to job category. An earlier publication presented results for women; here, we report the findings for men and discuss the overall patterns in both genders. The most consistent overall finding was an approximate doubling in relative risk for all four types of malignancies among male managers and related occupations. Several additional occupations were associated with elevated risk of one or more malignancies among men. These included cooks, waiters, and bartenders, and building caretakers and cleaners, for non-Hodgkin’s lymphoma; textile workers and machinery fitters for Hodgkin’s lymphoma; metal processors, material handlers, rubber workers, and painters for leukemia; and hairdressers, metal processors, tailors, electrical workers, and plumbers for multiple myeloma. The finding of increased risk of non-Hodgkin’s lymphoma among both male and female cooks, waiters, and bartenders has not been previously reported; nor has the elevated risk of leukemia among material handlers. Among people engaged in agriculture, those employed as tractor drivers and as “orchard, vineyard, and related tree and shrub workers” appeared to be at increased risk for hematolymphopoietic malignancies.

Somatic Mutations and Deletions of the E-Cadherin Gene Predict Poor Survival of Patients With Gastric Cancer

PURPOSE The prognosis of gastric cancer (GC) is poor, and the molecular pathogenesis players are vastly unknown. Surgery remains the primary option in GC treatment. The aim of this study was to investigate the impact of somatic CDH1 alterations in prognosis and survival of patients with GC. PATIENTS AND METHODS A series of patients with sporadic and familial GC (diffuse and intestinal; n = 246) were analyzed for somatic CDH1 mutations, promoter hypermethylation, and loss of heterozygosity (LOH) by polymerase chain reaction sequencing. E-cadherin protein expression was determined by immunohistochemistry. Associations between molecular, clinicopathologic, and survival data were analyzed. RESULTS CDH1 somatic alterations were found in approximately 30% of all patients with GC. Both histologic types of sporadic GC displayed LOH in 7.5%, mutations in 1.7%, and hypermethylation in 18.4% of patients. Primary tumors from hereditary diffuse GC, lacking germline CDH1 alterations, showed exclusively CDH1 promoter hypermethylation in 50% of patients. Familial intestinal GC (FIGC) tumors showed LOH in 9.4% and hypermethylation in 17.0%. CDH1 alterations did not associate with a particular pattern of E-cadherin expression. Importantly, the worst patient survival rate among all GCs analyzed was seen in patients with tumors carrying CDH1 structural alterations, preferentially those belonging to FIGC families. CONCLUSION CDH1 somatic alterations exist in all clinical settings and histotypes of GC and associate with different survival rates. Their screening at GC diagnosis may predict patient prognosis and is likely to improve management of patients with this disease.

Survival benefit of extended D2 lymphadenectomy in gastric cancer with involvement of second level lymph nodes: A longitudinal multicenter study

BackgroundThe survival benefit of extended lymphadenectomy in the surgical treatment of gastric cancer is still being debated. The aim of this longitudinal multicenter study was to evaluate long-term survival in a group of patients with involvement of second level lymph nodes, which would not have been removed in the case of a limited lymphadenectomy. Results were compared with those in patients with involvement of first level lymph nodes.MethodsBetween 1991 and 1997, 451 patients with primary gastric cancer underwent curative resection with extended lymphadenectomy at three surgical departments in Italy according to the rules of the Japanese Research Society for Gastric Cancer.ResultsIn 451 cases treated by extended lymphadenectomy, morbidity and mortality rates were 17.1% and 2%, respectively. In 126 patients (27.9%) (group A), metastases were found in lymph node stations 7 to 12; 109 patients (24.2%) had metastases confined to the first level (group B). Lymph node stations 7 and 8 showed the highest incidence of metastases in the second level (17.1% and 12.4%, respectively). A significant difference in 5-year survival was observed between group A and group B (32% vs. 54%;P=.0005). This difference disappeared when cases were stratified according to the number of positive lymph nodes. By multivariate analysis, only the number of positive lymph nodes (relative risk, 1.8;P<.0001) and the depth of invasion (relative risk. 2.1;P<.0001), but not the level of involved nodes, showed to be independent predictors of poor prognosis.ConclusionsJapanese-type extended lymphadenectomy yields low morbidity and mortality rates if performed in specialized centers. This procedure could provide a good probability of long-term survival, even for patients with involvement of regional lymph nodes.

Nuclear morphometry as an important prognostic factor in stage I renal cell carcinoma

Although 60% of Stage I renal carcinoma patients die from tumor within 5 years postoperatively, a considerable percentage survive that period. Nuclear grading can help to predict the outcome, but many of the patients are Grade 2, and the prognosis of this subclass is uncertain. Therefore, nuclear morphometry was carried out in 41 patients with Stage I renal cell carcinoma. Of these, 24 died within 5 years and 17 have survived that period. Using a mean nuclear area of 32 μm2 as the decision threshold, none of the 24 short‐term survivors are below that threshold and three of the long‐term survivors exceed that value (18% false‐positives) (99% confidence limit). Separate analysis with sets for learning and testing and Grade 2 patients gave similar results. The results show the essential prognostic value of morphometry in this set of patients with Stage I renal cell carcinoma.

Inactivation of the E-cadherin gene in sporadic diffuse-type gastric cancer.

Loss of the cell adhesion molecule E-cadherin has been observed in a variety of human carcinomas, and germline E-cadherin mutations have been found in several familial cases of diffuse gastric cancer. We sought to determine the prevalence and nature of E-cadherin alterations in “sporadic” gastric carcinomas. We performed comprehensive sequencing of the coding region, loss of heterozygosity (LOH) analysis, and immunohistochemical protein expression determination on 40 sporadic gastric adenocarcinomas. In total, 7 of 25 diffuse-type cancers harbored genetic alterations in the E-cadherin gene. Novel mutations predicted to significantly compromise protein function were found within 4 of these cancers, 2 of which harbored alterations resulting in biallelic inactivation of the gene product. Three diffuse cancers failed to amplify Exon 8 of E-cadherin, suggesting the presence of a homozygous abnormality. Notably, one germline E-cadherin mutation was also identified within these “sporadic” diffuse cancers. Significant gene mutations were not found in the 14 intestinal-type or histologically mixed cancer. Immunohistochemistry revealed aberrant or negative protein expression in seven diffuse-type tumors, four of which correlated with the genetic alterations. Both diffuse and intestinal-type tumors exhibited low rates of LOH, suggesting that allelic loss at the locus is not a common mechanism for E-cadherin inactivation during gastric tumorigenesis. Our observations suggest that inactivation of the E-cadherin gene occurs only in a subset of diffuse-type gastric cancers, as the majority of cases did not contain genetic alterations or identifiable protein abnormalities. Germline E-cadherin alterations, although rare, may underlie some diffuse gastric cancer cases that have important biologic and practical implications