Ki-ras mutations in exocrine pancreatic cancer: association with clinico-pathological characteristics and with tobacco and alcohol consumption. PANK-ras I Project Investigators.

The aims of this study were (i) to assess the prevalence and spectrum of codon 12 Ki-ras mutations in patients diagnosed with exocrine pancreatic cancer (EPC) in 2 general hospitals between 1980 and 1990, (ii) to analyze the association of this genetic alteration with clinical and pathological characteristics, and (iii) to determine the association of Ki-ras mutations with tobacco and alcohol consumption. DNA was amplified from paraffin-embedded tissue samples and mutations in codon 12 of Ki-ras were detected using the artificial RFLP technique. Cox proportional-hazards regression and unconditional logistic regression were applied. Codon 12 Ki-ras mutations were detected in 30 of 51 cases for which molecular results were available. The amino-acid substitutions were Asp (8), Val (6), and Arg (3). A double mutation, including always a Val, was detected in 5 cases. None of the 4 nonductal pancreatic neoplasms were mutated. The mutation prevalence was 79% in metastases and 54% in primary tumors. The risk of a mutated tumor was 3 times higher in alcohol drinkers than in non-drinkers, and a linear trend was apparent. When age, gender, hospital, and tobacco and alcohol consumption were taken into account, a high risk for mutations was detected in patients who only smoked and in patients who only drank, but less so in patients who both smoked and drank. These results raise novel hypotheses regarding the role of tobacco and alcohol in EPC.

Sex as a prognostic factor in gastric cancer.

The aim of this study was to assess whether survival of gastric cancer patients differed between males and females. Although it is well known that the incidence of gastric cancer is higher for men than for women, the existence of a sex-specific prognosis has seldom been addressed. Studies based on population registries have not assessed the role of stage and histology. Cases of histologically confirmed gastric carcinoma were obtained from three Spanish hospitals in Soria (n = 405), Barcelona (n = 249) and Mataró (n = 197). Differences in possible confounders were tested between men and women and survival analyses were performed separately by hospital. Cox's proportional hazards models were used to account for age, tumour stage, histology and tumour sub-location. Only in Mataró was a significant difference in the stage distribution observed between women and men, with a lower proportion of local stage tumours among women (P = 0.047). No statistically significant differences of histological type between men and women were observed in any of the centres. After adjusting for tumour stage and age, women were observed to have significantly better survival in Barcelona (female to male hazard ratio (HR) = 0.578, P < 0.001); this effect was marginal in Soria (HR = 0.788, P = 0.092) and non-significant in Matar-o (HR = 0.895, P = 0.54). Age-adjusted hazard ratios were calculated within each tumour stage. For Barcelona, the effect of better prognosis among women was most marked at local stage (HR = 0.320, P = 0.013), and in Soria at the regional stage (HR = 0.426, P = 0.002). Although in Mataró all HRs were below unity, none were statistically significant. Little effect was observed at the disseminated stage. The other covariables exerted no influence. Women appear to have a better prognosis than men, and the difference could be tumour stage dependent. Confirmation of these findings would give a valuable insight into gastric cancer growth and ultimately be of use in planning treatment.

[Agreement between information supplied by the patient and a family member on medical history, consumption of tobacco, alcohol and coffee and diet in cancer of the exocrine pancreas and extrahepatic biliary tract]. / Concordancia entre la información facilitada por el paciente y un familiar sobre antecedentes patológicos, consumo de tabaco, de alcohol, de café, y dieta en el cáncer de páncreas exocrino y del sistema biliar extrahepático.

OBJECTIVE: No study on mutations in the K-ras oncogene and cancer of the exocrine pancreas or cancer of the biliary system has analyzed the reliability of clinical and epidemiological information. METHODS: Agreement between patient and surrogate on factors potentially related to both tumours was evaluated within a multicentre prospective study. Interviews were personally administered to both patient and surrogate (N = 110 pairs). Agreement was examined via the simple kappa index (k), the weighted kappa index (kw), the percentage of simple agreement, and the percentages of positive and negative agreement. RESULTS: Agreement for medical history was excellent (k between 0.89 and 0.76), as it was for tobacco consumption (k = 0.98). Agreement was moderate for coffee consumption (k = 0.68), frequencies of food groups (kw from 0.66 to 0.38), and consumption of alcoholic drinks (k from 0.66 to 0.32). Surrogates indicated a higher consumption of alcohol than patients. CONCLUSION: Surrogates can be an alternative source of information when patients cannot be interviewed, but information on alcohol consumption should be treated with caution.

Ki-ras mutations as a prognostic factor in extrahepatic bile system cancer. PANK-ras I Project Investigators.

PURPOSE: To assess the prevalence and prognostic significance of Ki-ras codon 12 mutations in extrahepatic biliary system cancer (EBSC). PATIENTS AND METHODS: Patients diagnosed with EBSC between 1980 and 1990 (N = 111) were selected from two hospitals. DNA was amplified from paraffin-embedded tissues and mutations in codon 12 of Ki-ras were detected using the artificial restriction fragment-length polymorphism (RFLP) technique. RESULTS: Tissue was available from 68.5% of patients. The prevalence of mutations was 41%. There was no association between mutations and clinical and pathologic characteristics; however, mutations in Ki-ras were associated with survival, with a median survival duration of 7.7 months for patients with wild-type Ki-ras and 1.7 months for patients with mutated tumors (hazards ratio [HR] = 1.67; P = .075). Among patients with stage I to II tumors, the chance of dying of patients with the mutation was 7.8 times higher than that of patients without the mutation (P = .087); the corresponding HR for patients with stage III to IV disease was 2.9 (P = .003). After adjusting for age, tumor site, histology, differentiation, and stage, the HR for Ki-ras mutations was 2.12 (P = .026). CONCLUSION: Ki-ras codon 12 mutations are an independent prognostic indicator in patients with EBSC. Mutation detection may be of help in the management of these patients.

Diagnostic certainty and potential for misclassification in exocrine pancreatic cancer. PANKRAS I Project Investigations.

Whereas over the last decade epidemiologic studies on exocrine pancreatic cancer (EPC) continued to show a remarkable heterogeneity in diagnostic criteria applied to define caseness, the actual magnitude and consequences of misclassification remain largely unexplored. The objectives were: (1) to estimate the degree of certainty with which cases of EPC are diagnosed in the two participating hospitals (to this end a diagnostic certainty classification (DCC) was developed; (2) to test whether characteristics of cases differed by degree of diagnostic certainty; and (3) to assess what influence different definitions of case might have on risk estimates for tobacco and alcohol. All cases with a discharge diagnosis of EPC who attended at the Hospital del Mar between 1980-90 and at the Hospital Son Dureta between 1983-90 were identified through their respective tumor registries, and their clinical records were reviewed. Only 52% of 140 cases were classified in the group with a higher probability of EPC (group H). Diagnostic certainty appeared somewhat greater among women (age-adjusted odds ratio [ORa] 1.60, p = 0.18). Group H showed a higher proportion of cases with an interval from first symptom to diagnosis < or = 1 month (ORa = 2.38, p < 0.05) and the proportion of adenocarcinomas was slightly higher than in less certain cases (group L) (p = 0.051). A radical treatment was exclusively attempted in group H (p < 0.001). DCC cut-off points had a significant effect on the proportion of smokers and of alcohol drinkers, as well as on the percent of cases with pathological (cytohistological) confirmation. The proportion of cases unlikely to be of pancreatic origin in spite of having pathological confirmation was high enough to cause significant misclassification bias. Because past exposure to certain risk factors may differ among cases with different diagnostic certainty, we suggest to initially include in the case group patients who in spite of lacking pathological confirmation have strong clinical evidence supporting the diagnosis of EPC; subsequently, risk estimates should be computed across strata of diagnostic certainty to assess whether heterogeneity exists. In exocrine pancreatic cancer the impact of misclassification of disease status upon etiologic and prognostic estimates deserves at least as much attention as misclassification of exposure.

Cancer survival and the duration of symptoms. An analysis of possible forms of the risk function. ISDS II Project Investigators.

The time interval between onset of symptoms and the diagnosis of cancer [symptom to diagnosis interval (SDI), or duration of symptoms] is a highly complex variable reflecting patient behaviour, the clinical course, the functioning of the health system and tumour biology. In order to assess possible forms of the risk function of SDI upon cancer survival whilst taking into account the effects of age, sex, tumour site and stage at diagnosis, 1887 symptomatic cases of lung, breast, stomach, colon, rectal, bladder cancer and lymphomas registered in the Tumour Registry of the Hospital del Mar (Barcelona) were analysed by means of survival curves and Cox proportional hazards regression. Subjects (mean age 64 years) were followed for a median length of 15 months after diagnosis (follow-up rate 93.5%). SDI showed a weak relationship with tumour stage at diagnosis and with survival: out of the seven sites studied, only in breast cancer was tumour extension at diagnosis significantly influenced by duration of symptoms, and only lung and rectal cancers showed a detectable form of the risk function of SDI upon survival; neither was linear, and for rectal cancer the relationship was complexly related with tumour stage. Hence, results show that forms of the risk function of duration of symptoms on cancer survival are specific to tumour sites, and that the interval should not be represented as a linear, continuous term. Studies analysing more complex sets of factors, processes and forms of the SDI function are needed.