Roger Stenling

Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).

It is considered that fruit and vegetable (F&V) protect against oesophagus and gastric cancer (GC). However, 2 recent meta‐analyses suggest that the strength of association on GC seems to be weaker for vegetables than for fruit and weaker in cohort than in case‐control studies. No evidence exists from cohort studies about adenocarcinoma of oesophagus (ACO). In 521,457 men and women participating in the EPIC cohort in 10 European countries, information of diet and lifestyle was collected at baseline. After an average of 6.5 years of follow‐up, a total of 330 GC and 65 ACO, confirmed and classified by a panel of pathologists, was used for the analysis. We examined the relation between F&V intake and GC and ACO. A calibration study in a sub‐sample was used to control diet measurement errors. In a sub‐sample of cases and a random sample of controls, antibodies against Helicobacter pylori (Hp) were measured and interactions with F&V were examined in a nested case‐control study. We observed no association with total vegetable intake or specific groups of vegetables and GC risk, except for the intestinal type, where a negative association is possible regarding total vegetable (calibrated HR 0.66; 95% CI 0.35–1.22 per 100 g increase) and onion and garlic intake (calibrated HR 0.70; 95% CI 0.38–1.29 per 10 g increase). No evidence of association between fresh fruit intake and GC risk was observed. We found a negative but non significant association between citrus fruit intake and the cardia site (calibrated HR 0.77; 95% CI 0.47–1.22 per 100 g increase) while no association was observed with the non‐cardia site. Regarding ACO, we found a non significant negative association for vegetable intake and for citrus intake (calibrated HRs 0.72; 95% CI 0.32–1.64 and 0.77; 95% CI 0.46–1.28 per 100 and 50 g increase, respectively). It seems that Hp infection does not modify the effect of F&V intake. Our study supports a possible protective role of vegetable intake in the intestinal type of GC and the ACO. Citrus fruit consumption may have a role in the protection against cardia GC and ACO.

High Macrophage Infiltration along the Tumor Front Correlates with Improved Survival in Colon Cancer

Purpose: The role of macrophages in tumorigenesis is complex because they can both prevent and promote tumor development. Experimental Design: Four hundred forty-six colorectal cancer specimens were stained with the pan-monocyte/macrophage marker CD68, and average infiltration along the tumor front was semiquantitatively evaluated using a four-grade scale. Each section was similarly scored for the presence of CD68 hotspots. Some aspects of macrophage-tumor cell interactions were also studied using in vitro coculture systems. Results: Including all patients, regardless of surgical outcome and localization, survival increased incrementally with CD68TFMean infiltration grade (P = 0.0001) but not in curatively resected colon cancers (P = 0.28). CD68 hotspot score (CD68TFHotspot) was divided into high and low. A high hotspot score conferred a highly significant survival advantage also in curatively resected colon cancer cases (n = 199, P = 0.0002) but not in rectal cancers. CD68TFHotspot high turned out as an independent prognostic marker for colon cancer in multivariate analyses including gender, age, localization, grade, stage, tumor type, and lymphocytes at the tumor front, conferring a relative risk of 0.49 (P = 0.007). In vitro coculture experiments, using phorbol 12-myristate 13-acetate–activated U937 cells as macrophage model, revealed that a high ratio of macrophages to colon cancer cells inhibited cancer cell growth. This was partially dependent on cell-to-cell contact, whereas Boyden chamber cocultivation without cell-to-cell contact promoted cancer cell spread. Conclusions: In conclusion, our data indicate that a dense macrophage infiltration at the tumor front positively influences prognosis in colon cancer and that the degree of cell-to-cell contact may influence the balance between protumorigenic and antitumorigenic properties of macrophages.

Low folate levels may protect against colorectal cancer

Background and aims: Dietary folate is believed to protect against colorectal cancer (CRC). However, few studies have addressed the role of circulating levels of folate. The aim of this study was to relate prediagnostic plasma folate and homocysteine concentrations and the methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms to the risk of developing CRC. Subjects: Subjects were 226 cases and 437 matched referents from the population based Northern Sweden Health and Disease Cohort. Results: We observed a bell-shaped association between plasma folate concentrations and CRC risk; multivariate odds ratio for middle versus lowest quintile 2.00 (95% confidence interval (CI) 1.13–3.56). In subjects with follow up times greater than the median of 4.2 years however, plasma folate concentrations were strongly positively related to CRC risk; multivariate odds ratio for highest versus lowest quintile 3.87 (95% CI 1.52–9.87; p trend = 0.007). Homocysteine was not associated with CRC risk. Multivariate odds ratios for the MTHFR polymorphisms were, for 677 TT versus CC, 0.41 (95% CI 0.19–0.85; p trend = 0.062), and for 1298 CC versus AA, 1.62 (95% CI 0.94–2.81; p trend = 0.028). Interaction analysis suggested that the result for 1298A>C may have been largely due to linkage disequilibrium with 677C>T. The reduced CRC risk in 677 TT homozygotes was independent of plasma folate status. Conclusions: Our findings suggest a decreased CRC risk in subjects with low folate status. This possibility of a detrimental component to the role of folate in carcinogenesis could have implications in the ongoing debate in Europe concerning mandatory folate fortification of foods.

DNA content in renal cell carcinoma with reference to tumor heterogeneity

DNA content was successfully determined by flow cytometry in 196 tissue samples from 25 renal cell carcinomas. Twelve tumors (48%) were homogenously diploid/near‐diploid, whereas 11 tumors were aneuploid and 2 tumors were polyploid. Cell clones with different DNA content were found in 11 tumors demonstrating a considerable heterogeneity in the non‐diploid tumors; 9 of these 11 heterogenous tumors contained both aneuploid and diploid cell clones. Tumor samples morphologically classified as grade 1 and 2 were 98% diploid and grade 4 samples were 78% aneuploid. No correlation between DNA distribution and morphologic grade was found for grade 3 tumor samples. Tumor proliferation rate, as determined by the fraction of cells in S‐phase, was significantly higher in aneuploid samples compared to normal kidney tissue samples and diploid tumor samples.

Are lymph node micrometastases of any clinical significance in dukes stages A and B colorectal cancer

PURPOSE: The aim was to investigate the significance of lymph node micrometastases in Dukes Stages A and B colorectal cancer. METHODS: Archival specimens were examined from 147 patients (96 colon, 51 rectum; 44 Stage A, 103 Stage B) who had surgery between 1987 and 1994. One lymph node section from each node (colon, 1–11; median, 4; rectum, 1–15; median, 3) was examined with use of an anticytokeratin antibody. RESULTS: Forty-seven (32 percent) patients had micrometastases. At follow-up in June 1996, 23 patients had died of cancer or with known tumor relapse, after a median time of 28 (range, 5–67) months; 8 of 47 (17 percent) patients had micrometastases, 15 of 100 (15 percent) did not. No statistically significant differences were observed according to micrometastases when the results were analyzed with respect to Dukes stage or survival time. The median survival time of living patients with micrometastases was 48 (range, 18–97) months, and for patients without micrometastases, 48 (range, 19–111) months. Six of 96 living patients had a tumor relapse; three of these displayed micrometastases. CONCLUSION: Lymph node micrometastases are not a useful prognostic marker in Dukes Stages A and B and do not imply different strategies for additional therapy or follow-up.

Adherence to a Mediterranean diet and risk of gastric adenocarcinoma within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study

BACKGROUND The Mediterranean dietary pattern is believed to protect against cancer, although evidence from cohort studies that have examined particular cancer sites is limited. OBJECTIVE We aimed to explore the association between adherence to a relative Mediterranean diet (rMED) and incident gastric adenocarcinoma (GC) within the European Prospective Investigation into Cancer and Nutrition study. DESIGN The study included 485,044 subjects (144,577 men) aged 35-70 y from 10 European countries. At recruitment, dietary and lifestyle information was collected. An 18-unit rMED score, incorporating 9 key components of the Mediterranean diet, was used to estimate rMED adherence. The association between rMED and GC with respect to anatomic location (cardia and noncardia) and histologic types (diffuse and intestinal) was investigated. A calibration study in a subsample was used to control for dietary measurement error. RESULTS After a mean follow-up of 8.9 y, 449 validated incident GC cases were identified and used in the analysis. After stratification by center and age and adjustment for recognized cancer risk factors, high compared with low rMED adherence was associated with a significant reduction in GC risk (hazard ratio: 0.67; 95% CI: 0.47, 0.94). A 1-unit increase in the rMED score was associated with a decreased risk of GC of 5% (95% CI: 0.91, 0.99). There was no evidence of heterogeneity between different anatomic locations or histologic types. The calibrated results showed similar trends (overall hazard ratio for GC: 0.93; 95% CI: 0.89, 0.99). CONCLUSION Greater adherence to an rMED is associated with a significant reduction in the risk of incident GC.

Prognostic significance of the Heidelberg classification of renal cell carcinoma.

Objective: The specific genetic alterations characterising renal cell carcinoma (RCC) have lead to the recognition of distinctive types of tumours. In a large material of patients, the prognostic and clinical information of these different tumour types were evaluated. Methods: Tumours from 186 patients were evaluated retrospectively according to the guidelines given by the Heidelberg Classification Conference. All patients were primarily nephrectomised and TNM staged, and the follow-up times for alive patients varied between 44 and 174 months. Results: The material consisted of 145 conventional (non-papillary), 25 papillary, 12 chromophobe and 4 unclassified RCCs. There was no difference in tumour size between the different RCC types. Among patients with conventional RCC, 37% had distant metastases at the time of diagnosis, significantly more frequently than 16% in patients with papillary and 8% in chromophobe RCC (p = 0.044 and 0.048, respectively). Conventional RCC more frequently had vein invasion compared with papillary RCC (p = 0.009). Patients with chromophobe and papillary RCC survived significantly longer than patients with conventional RCC (p = 0.017 and 0.031, respectively). Conclusions: A significant difference in clinical behaviour between the different RCC types was found. Patients with conventional RCC had a higher incidence of metastases, vein invasion and had adverse survival compared with papillary and chromophobe RCCs. Thus, the RCC types recognised by specific genetic alterations seem to represent different malignant phenotypes.

Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor.

The aim of this study was to relate the density of tumor infiltrating T cells to cancer-specific survival in colorectal cancer, taking into consideration the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) screening status. The T-cell marker CD3 was stained by immunohistochemistry in 484 archival tumor tissue samples. T-cell density was semiquantitatively estimated and scored 1–4 in the tumor front and center (T cells in stroma), and intraepithelially (T cells infiltrating tumor cell nests). Total CD3 score was calculated as the sum of the three CD3 scores (range 3–12). MSI screening status was assessed by immunohistochemistry. CIMP status was determined by quantitative real-time PCR (MethyLight) using an eight-gene panel. We found that patients whose tumors were highly infiltrated by T cells (total CD3 score ≥7) had longer survival compared with patients with poorly infiltrated tumors (total CD3 score ≤4). This finding was statistically significant in multivariate analyses (multivariate hazard ratio, 0.57; 95% confidence interval, 0.31–1.00). Importantly, the finding was consistent in rectal cancer patients treated with preoperative radiotherapy. Although microsatellite unstable tumor patients are generally considered to have better prognosis, we found no difference in survival between microsatellite unstable and microsatellite stable (MSS) colorectal cancer patients with similar total CD3 scores. Patients with MSS tumors highly infiltrated by T cells had better prognosis compared with intermediately or poorly infiltrated microsatellite unstable tumors (log rank P=0.013). Regarding CIMP status, CIMP-low was associated with particularly poor prognosis in patients with poorly infiltrated tumors (multivariate hazard ratio for CIMP-low versus CIMP-negative, 3.07; 95% confidence interval, 1.53–6.15). However, some subset analyses suffered from low power and are in need of confirmation by independent studies. In conclusion, patients whose tumors are highly infiltrated by T cells have a beneficial prognosis, regardless of MSI, whereas the role of CIMP status in this context is less clear.

Vein Invasion in Renal Cell Carcinoma: Impact on Metastatic Behavior and Survival

PURPOSE The development of a thrombus extending into the veins is well recognized in renal cell carcinoma. We investigated the hypothesis that vein invasion alone has no adverse impact on survival but is a highly negative factor in other tumors. MATERIALS AND METHODS In 200 consecutive patients invasion of the renal vein and vena cava was evaluated and compared with the clinical course. RESULTS A total of 26 patients had vena caval and 47 had renal vein invasion. Patients with venous invasion had a significantly shorter survival but no survival difference was demonstrated based on the level of involvement. CONCLUSIONS Our study indicates that vein invasion itself seems to be an important prognostic factor in renal cell carcinoma.

Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition

Background: Increasing evidence suggests that general obesity [measured by body mass index (BMI)] is positively associated with risk of esophageal adenocarcinoma (EAC). In contrast, previous studies have shown inverse relations with esophageal squamous cell carcinoma (ESCC). However, it is still unclear whether body fat distribution, particularly abdominal obesity, is associated with each type of esophageal cancer. Methods: We applied multivariable adjusted Cox proportional hazards regression to investigate the association between anthropometric measures and risk of EAC and ESCC among 346,554 men and women participating in the European Prospective Investigation into Cancer and Nutrition. All statistical tests were two sided. Results: During 8.9 years of follow-up, we documented 88 incident cases of EAC and 110 cases of ESCC. BMI, waist circumference, and waist-to-hip ratio (WHR) were positively associated with EAC risk [highest versus lowest quintile; relative risk (RR), 2.60; 95% confidence interval (95% CI), 1.23-5.51; Ptrend < 0.01; RR, 3.07; 95% CI, 1.35-6.98; Ptrend < 0.003; and RR, 2.12; 95% CI, 0.98-4.57; Ptrend < 0.004]. In contrast, BMI and waist circumference were inversely related to ESCC risk, whereas WHR showed no association with ESCC. In stratified analyses, BMI and waist circumference were significantly inversely related to ESCC only among smokers but not among nonsmokers. However, when controlled for BMI, we found positive associations for waist circumference and WHR with ESCC, and these associations were observed among smokers and nonsmokers. Conclusion: General and abdominal obesity were associated with higher EAC risk. Further, our study suggests that particularly an abdominal body fat distribution might also be a risk factor for ESCC. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2079–89)