Introduction and Literature Review: Pancreatic cancer is often diagnosed in an advanced/metastatic stage, as it is a very aggressive type of cancer. The prognosis of pancreatic cancer is extremely unfavorable. The mean survival rate for patients with metastatic pancreatic adenocarcinoma is 3-6 months. Stage IV pancreatic cancer has a five-year survival rate of 1.3% to 13%. This article presents recent data regarding the oncologic management of metastatic pancreatic cancer. Case presentation: We present the case of a female patient who was 49 years old at the time of diagnosis, in June 2021. The patient was diagnosed with stage IV pancreatic neoplasm (due to liver metastases). The diagnosis was made by histopathological and immunohistochemical examination, which corroborated imaging investigations. The patient underwent four lines of chemotherapy between July 2021 and July 2024, undergoing partial response to the disease. The patient is a long-term survivor of metastatic pancreatic cancer (3 years in July 2024). Discussions: the peculiarity of this case is long-term survival (3 years and a month at the date when this article is being written) in a patient with pancreatic cancer and liver metastases. Conclusions: histopathological type, good performance status, CEA, and CA tumor markers 19.9 within normal limits may be favorable prognostic factors for long-term survival in metastatic pancreatic carcinoma.

In this study, we investigated which N staging system was the most accurate at predicting survival in pancreatic cancer patients.Lymph node (LN) metastasis is known to be one of the important prognostic factors in resected pancreatic cancer. There are several LN evaluation systems to predict oncologic impact.From January 1992 to December 2014, 77 medical records of patients who underwent radical pancreatectomy for left-sided pancreatic cancer were reviewed retrospectively. Clinicopathologic variables including pN stage, total number of retrieved LNs (N-RLN), lymph node ratio (LNR), and absolute number of LN metastases (N-LNmet) were evaluated. Disease-free survival (DFS) and disease-specific survival (DSS) were analyzed according to these 4 LN staging systems.In univariate analysis, pN stage (pN0 vs pN1: 17.5 months vs 7.9 months, P = 0.001), LNR (<0.08 vs ≥0.08: 17.5 months vs 4.4 months, P < 0.001), and N-LNmet (#N = 0 vs #N = 1 vs #N≥2: 17.5 months vs 11.0 months vs 6.4 months, P = 0.002) had a significant effect on DFS, whereas the pN stage (pN0 vs pN1: 35.3 months vs 16.7 months, P = 0.001), LNR (<0.08 vs ≥0.08: 37.1 months vs 15.0 months, P < 0.001), and N-LNmet (#N = 0 vs #N = 1 vs #N≥2: 35.3 months vs 18.4 months vs 16.4 months, P = 0.001) had a significant effect on DSS. In multivariate analysis, N-LNmet (#N≥2) was identified as an independent prognostic factor of oncologic outcome (DFS and DSS: Exp (β) = 2.83, P = 0.001, and Exp (β) = 3.17, P = 0.001, respectively).Absolute number of lymph node metastases predicted oncologic outcome in resected left-sided pancreatic cancer patients.

Owing to aggressiveness and chemoresistance, pancreatic ductal adenocarcinoma (PDAC) is characterised by a poor prognosis. To address this disease-spe-cific dilemma we aimed to establish animal models, which can be used for identifying new specific tumor markers, as well as serving as tools for potential therapeutic approaches. From a panel of sixteen pancreatic cancer cell lines, two human (Suit2-007 and Suit2-013) and a rat (ASML) cell line were selected for their properties to grow in the liver of male RNU rats and mimic liver metastasis of PDAC. For better monitoring of metastatic tumor growth in vivo, all three pancreatic cancer cell lines were stably transfected with eGFP and luciferase marker genes. In addition, the mRNA expression profile of 13 human PDAC cell lines was analyzed by BeadChip array analysis. Only 33 genes and 5 signaling pathways were identified as significantly associated with the ability of the cell lines to grow initially and/or consistently in rat liver. Only a minority of these genes (osteopontin, matrix metalloproteinase-1 and insulin-like growth factor 1) has been intensively studied and shown to be closely related to cancer progression. The function of the remaining 30 genes ranges from moderate to poorly investigated, and their function in cancer progression is still unclear. The ensuing three pancreatic cancer liver metastasis models vary in their aggressiveness and macroscopic growth. They will be used for preclinical evaluation of new therapeutic approaches aiming at the genes identified.

Primary adenocarcinomas removed by pancreatoduodenectomy originate from the duodenum (DC), ampulla (AC), distal bile duct (DBC), or pancreas (PC). Pathobiology, staging, survival, and adjuvant chemotherapy vary among these cancers. The proximity of the structures of possible origin renders it difficult to obtain a correct diagnosis, which might lead to inconsistencies in reported data and inappropriate adjuvant treatment.

Records of 207 patients undergoing pancreatoduodenectomy (1998-2009) for periampullary adenocarcinoma were reviewed. Routine histopathology reports of tumour origin performed by multiple pathologists were independently re-evaluated based on predetermined criteria by two experienced pancreatic pathologists.

Slide review changed the diagnosis in 55 (27%) patients. After reclassification, final distribution was 29 (14%) DC, 52 (25%) AC, 57 (28%) DBC, and 69 (33%) PC. The diagnosis was revised in 4 (14%) DC, 7 (17%) AC, 30 (53%) DBC and 14 (19%) PC. The underestimation of DBC during routine histopathology was caused by misinterpretation of DBC either PC or AC. Misclassification of PC was mainly due to erroneous diagnosis of AC. Reassignment of tumour origin caused no significant changes in survival within cancer type, but resulted in a significant difference in survival between DBC and PC (p = 0.004).

Specialist slide review resulted in reassignment of tumour origin in 27% of periampullary adenocarcinomas. Distal bile duct cancer was found to be most frequently misdiagnosed (53%). Correct diagnosis of tumour origin is crucial for data quality, appropriate adjuvant therapy, and patient inclusion in clinical trials.

Assessment of the origin of adenocarcinoma in pancreatoduodenectomy specimens (pancreatic, ampullary or biliary) and resection margin status is not performed in a consistent manner in different centres. The aim of this review was to identify the impact of such variations on patient outcome.

A systematic literature search for articles on pancreatic, ampullary, distal bile duct and periampullary cancer was performed, with special attention to data on resection margin status, pathological examination and outcome.

The frequent reclassification of tumour origin following slide review, and the wide variation in published incidence of pancreatic (33-89 per cent), ampullary (5-42 per cent) and distal bile duct (5-38 per cent) cancers indicate that the histopathological distinction between the three cancer groups is less accurate than generally believed. Recent studies have shown that the wide range of rates of microscopic margin involvement (R1) in pancreatoduodenectomy specimens (18-85, 0-27 and 0-72 per cent respectively for pancreatic, ampullary and distal bile duct cancers) is mainly caused by differences in pathological assessment rather than surgical practice and patient selection. As a consequence of the existing inconsistency in reporting of these data items, the clinical significance of microscopic margin involvement in each of the three cancer groups remains unclear.

Inaccurate and inconsistent distinction between pancreatic, ampullary and distal bile duct cancer, combined with inaccuracies in resection margin assessment, results in obfuscation of key clinicopathological data. Specimen dissection technique plays a key role in the quality of the assessment of both tumour origin and margin status. Unless the pathological examination is meticulous and standardized, comparison of results between centres and observations in multicentre trials will remain of limited value.

To analyze the impact of pancreatitis-mimicking, concomitant alterations on intraoperative assessment of curative resectability, the anatomical site of irresectability, and outcome after nonintentional R2 resection in pancreatic cancer.

Of 1,099 patients subjected to pancreatic resection for cancer, 40 (4%) underwent R2 resection (group A). The site where tumors turned out to be irresectable and the coincident presence of potentially misleading, fibro-desmoplastic alterations were analyzed. Outcome after resection was compared with 40 bypass patients matched for age, gender, histopathology, and use of additive chemotherapy (group B).

R2 resection was due to misjudgment regarding resectability in 38 patients (95%) and to uncontrollable hemorrhage in 2 patients (5%). Group A patients had significantly longer operative times (P < 0.0001), required more blood units (P < 0.0001), and had longer hospital stay than group B patients (P = 0.049). Despite a significantly higher relaparotomy rate of 20% (n = 8) in group A versus 5% (n = 2) in group B, perioperative mortality was equal (n = 2, each). Median survival was 11.5 months in group A and 7.5 months in group B (P = 0.014). "Pancreatitis-like" lesions were assessed in 70% (n = 28/40, group A) and 25% (10/40, group B; P = 0.014). The superior mesenteric artery proximal to its jejunal branches was the most likely site of irresectability (60%), followed by its peripheral course (22.5%) and the lower aspects of the celiac trunk (17.5%).

Concomitant "pancreatitis-like" alterations hamper the assessment of local resectability in pancreatic cancer. Although palliative resection results in elevated perioperative morbidity compared with bypass procedures, mortality is equal, while survival is prolonged.

Worldwide survival data for ductal adenocarcinoma of the pancreas are the lowest among the 60 most frequent types of organ cancers. Hence published data on long time survivors of this disease are controversial. We performed a nationwide study comprising all Finnish patients diagnosed with pancreatic cancer in the period 1990-1996 who survived for at least five years after diagnosis.

Data on patients registered as five year survivors of pancreatic cancer were obtained from the Finnish Cancer Registry and Statistics Finland. Slides or paraffin blocks were collected from patients recorded as having histologically proven pancreatic ductal adenocarcinoma (PDAC) and were re-evaluated in a double blind fashion by three pathologists with special expertise in pancreatic pathology.

Between 1990 and 1996, the Finnish Cancer Registry recorded 4922 pancreatic cancer patients, 89 of whom survived for at least five years. Reviewing this series of patients revealed 45 (49%) non-PDACs and 18 cases without histological verification. In 26 patients recorded as having histologically proven PDAC, re-evaluation of histological specimens confirmed PDAC in only 10 patients.

This study indicates that (1) the prognosis of PDAC remains poor and (2) careful histopathological review of all patients with pancreatic cancer is mandatory if survival data are to be meaningful.

In both pancreatic cancer and chronic pancreatitis, there is enhanced expression of mitogenic growth factors and their tyrosine kinase receptors, which have the capacity to activate mitogen-activated protein kinase (MAPK). In view of the important role of MAPK kinase phosphatase (MKP)-1 in the regulation of MAPK activation, the expression and functional role of MKP-1 was analyzed.

Pancreatic tissues were analyzed by Northern blotting, Western blotting, and immunohistochemistry. Pancreatic cancer cells were transfected with a full-length MKP-1 antisense construct. Growth characteristics and tumorigenicity in vivo and the effects of mitogenic growth factors on cell growth and MAPK activation were determined in transfected and control cells.

MKP-1 messenger RNA (mRNA) levels were increased in pancreatic cancer and chronic pancreatitis (CP) tissues. Moderate to strong MKP-1 immunoreactivity was present in the cancer cells, ductal cells of pancreatic intraepithelial neoplasia, and in tubular complexes in CP. Down-regulation of MKP-1 resulted in decreased anchorage-dependent and -independent growth of pancreatic cancer cells, and decreased tumorigenicity in a nude mouse tumor model. MKP-1 down-regulation led to decreased proliferation and sustained MAPK activation in response to mitogens.

Suppression of MKP-1 expression reduces the tumorigenicity of pancreatic cancer cells in vivo, suggesting that MKP-1 contributes to enhanced mitogenic signaling in pancreatic cancer cells.

Pancreatic cancer is still one of the major health problems because of its rising incidence and the modest therapeutic results. The paper surveys the statistical data, the risk factors, the preneoplastic ductal lesions, the hormonal sensitivity, the possible transdifferentiation in the endocrine and exocrine parts and the possibilities for chemoprevention. Hungary is peculiar among the European countries because during the last 50 years the incidence of pancreatic cancer has displayed a 15-fold increase. Apart from smoking, additional risk factors seem to be important, and recently a puzzling association between Helicobacter pylori seropositivity and pancreatic cancer was found. First-degree relatives of patients with pancreatic cancer are also at increased risk of this tumor. The term pancreatic intraepithelial neoplasia (PanIN) seems yet to be established, but the dynamics of these lesions needs to be further elucidated. Several lines of firmly established data indicate the hormonal sensitivity of this tumor, but still an unexplained discrepancy exists between the experimental and the clinical results. In addition to the somatostatin analogs, anti-gastrin vaccine is being tested. The mixed exocrine-endocrine tumors might suggest a real possibility of transdifferentiation between different compartments of the pancreas. Finally, the paper outlines the available data about the possibility of chemoprevention, including the role of cyclooxygenase inhibitors.

Pancreatic cancer cells are usually resistant to apoptosis mediated by intrinsic or extrinsic factors. BAG-3 (Bis, CAIR), which was identified as a BAG-1-related protein, is a novel modulator of cellular anti-apoptotic activity that functions through its interaction with Bcl-2. In this study we analyzed BAG-3 expression in human pancreatic cancer tissues and cell lines. BAG-3 mRNA was expressed at moderate to high levels in all pancreatic cancer samples, but at low levels in normal pancreas tissues. In situ hybridization and immunohistochemistry analysis revealed that BAG-3 was present in the cancer cells within the pancreatic tumor mass. When BAG-3 mRNA was analyzed in other gastrointestinal cancers (hepatocellular carcinoma; esophageal, stomach and colon cancer), no difference was found from their corresponding normal controls. In pancreatic cancer cells, BAG-3 mRNA expression levels were strongly induced after heat stress, but not in response to members of the tumor necrosis factor (TNF)-alpha family (TNF-alpha, TRAIL, FasL). These findings indicate that in pancreatic cancer, in contrast to other gastrointestinal malignancies, increased levels of BAG-3 might function to block apoptosis. This characteristic of pancreatic cancer might contribute to its more aggressive growth behavior and poor responsiveness to treatment in vivo.

Despite of recent improvements in the treatment of many malignant diseases, pancreatic ductal adenocarcinoma is still a disease with an extremely poor prognosis with current modes of treatment. Gene therapy has been suggested as a novel approach also against pancreatic cancer. Previous studies have been carried out predominantly with immunodeficient animal models and with tumors growing in environments other than the pancreas. We have attempted to mimic a more clinically relevant situation and investigated suicide gene therapy strategy for experimental pancreatic cancer in animals with an intact immune system.

We used herpes simplex virus thymidine kinase (HSV-tk) and ganciclovir (GCV) strategy in both in vitro and in vivo settings.

In vitro studies demonstrated that retro- as well as adenovirally transduced HSV-tk-positive DSL-6A/C1 rat pancreatic carcinoma cells were sensitive to low concentrations of GCV when compared with parental, nontransduced cells. In addition, a strong bystander effect was observed. In in vivo studies, subcutaneously transplanted HSV-tk-positive DSL-6A/C1 cells were killed after GCV treatment, whereas parental, HSV-tk-negative cells continued to grow and developed into ductal adenocarcinomas. In in vivo HSV-tk-transduced pancreatic tumors, GCV treatment caused tumor necrosis and the necrosis volume was significantly more extensive when compared with control groups.

HSV-tk gene transfer followed by GCV treatment is efficient in killing pancreatic cancer cells in vitro, in a transduced subcutaneous tumor model, as well as in in vivo transduced pancreatic tumors using an immunocompetent animal model. These results highlight the potential of gene therapy to treat experimental pancreatic cancer.

Despite of recent improvements in the treatment of many malignant diseases, pancreatic ductal adenocarcinoma is still a disease with an extremely poor prognosis with current modes of treatment. Gene therapy has been suggested as a novel approach also against pancreatic cancer. Previous studies have been carried out predominantly with immunodeficient animal models and with tumors growing in environments other than the pancreas. We have attempted to mimic a more clinically relevant situation and investigated suicide gene therapy strategy for experimental pancreatic cancer in animals with an intact immune system.

We used herpes simplex virus thymidine kinase (HSV-tk) and ganciclovir (GCV) strategy in both in vitro and in vivo settings.

In vitro studies demonstrated that retro- as well as adenovirally transduced HSV-tk-positive DSL-6A/C1 rat pancreatic carcinoma cells were sensitive to low concentrations of GCV when compared with parental, nontransduced cells. In addition, a strong bystander effect was observed. In in vivo studies, subcutaneously transplanted HSV-tk-positive DSL-6A/C1 cells were killed after GCV treatment, whereas parental, HSV-tk-negative cells continued to grow and developed into ductal adenocarcinomas. In in vivo HSV-tk-transduced pancreatic tumors, GCV treatment caused tumor necrosis and the necrosis volume was significantly more extensive when compared with control groups.

HSV-tk gene transfer followed by GCV treatment is efficient in killing pancreatic cancer cells in vitro, in a transduced subcutaneous tumor model, as well as in in vivo transduced pancreatic tumors using an immunocompetent animal model. These results highlight the potential of gene therapy to treat experimental pancreatic cancer.

The aim was to analyse the magnitude, direction and predictors of change in the main hospital discharge diagnosis (HDD) after a clinical expert review, among patients included in a multicentre molecular epidemiologic study of biliopancreatic diseases.

A total of 602 patients with a suspicion diagnosis of pancreas cancer (PC), cancer of the extrahepatic biliary system (CEBS) or benign biliopancreatic pathologies (BPP) were prospectively recruited at five general hospitals. A structured form was used to collect information from medical records. A panel of experts revised all diagnostic information and established the main clinicopathological diagnosis (CPD) by consensus.

Of the 204 cases with a HDD of PC, 176 (86%) were deemed to have a CPD of PC, eight of CEBS, twelve a neoplasm of different origin, four BPP and four syndromic diagnoses. Thus, 28 cases (14%) were false positives. Of the 129 patients with a HDD of CEBS, 15 (12%) were false positives. Nine of the 396 cases with a HDD of non-PC (2%) had a CPD of PC (false negatives), whilst 14 of 471 patients with a HDD of non-CEBS (3%) were deemed to have CEBS. Overall, sensitivity and specificity of HDD for PC were, respectively, 95 and 93%, and for CEBS, 89 and 97%. Cytohistological confirmation and laparotomy were independent predictors of diagnostic change.

Validity of the HDD was high, but its association with some clinical variables suggests that sole reliance on HDD can significantly bias results, and highlights the need to review all HDDs. Alternatively, only patients at high risk of misdiagnosis could be reviewed: primarily, those lacking a cytohistological diagnosis or a laparotomy. No exclusions appear warranted solely on the basis of age, gender or tumour spread.

Primary prevention of pancreatic cancer and public health measures to reduce its incidence are dependent on data from epidemiological studies. Currently, the only definite risk factor is smoking, although a diet rich in fruit and vegetables may be protective. The K-ras mutation may have a role in diagnosis and screening.

Epidemiologic studies on exocrine pancreatic cancer show a large heterogeneity in diagnostic criteria applied to define "caseness." Reanalyses conducted after review of diagnostic information have yielded substantially different results than those based on more crude classifications of disease. During a multicenter prospective study on mutations in the K-ras gene in pancreatic and biliary diseases, hospital diagnoses from 602 patients were reviewed by a panel of experts. There were two main motivations to do so: a generic interest for the quality of the diagnostic data, and the anticipation that a firm diagnosis could be needed to assess whether patients whose tumors did not harbor the mutation were true negatives or false negatives. In addition, the review of diagnoses was helpful to minimize tissue misclassification, and it had a high educational value for clinicians and epidemiologists. This article illustrates why and how this was so through a brief presentation of the 10 most significant cases. With respect to selection and classification of subjects, the main issues that studies on pancreatic cancer need to address are the differential diagnosis of exocrine pancreatic cancer and pancreatitis, the differential diagnosis of exocrine pancreatic cancer and other abdominal tumors, and the use of survival as a hallmark of pancreatic cancer. In epidemiologic studies of pancreatic cancer, it is warranted that a panel of experts centrally reviews all the existing diagnostic evidence (cytohistological and other) of all patients, regardless of whether they have cytohistological confirmation and of their hospital discharge diagnosis.

This review analyses the current state of knowledge and understanding concerning the optimum treatment and therapeutic management of patients who suffer from pancreatic cancer. It outlines recent advances in scientific understanding and assesses their potential future value to clinicians in confronting this disease. Despite a significant expansion in scientific knowledge relating to factors underlying the early development of pancreatic carcinoma, the clinician continues to be restricted to a severely limited therapeutic armoury for this disease. Local therapies (surgery and radiation) are inevitably of limited value in the face of a disease that is normally encountered at a stage where metastasis is already highly developed. Despite such limitations, however, surgery performed in specialist units may be of value for 10-20% of patients, with a 5-year survival rate in such units of between 10 and 24%. This may be improved even further by appropriate use of adjuvant treatment. The advanced stage of the disease when normally encountered emphasizes the potential value of systemic treatment in this therapeutic area. Unfortunately systemic treatment (chemotherapy) has been found to be ineffective to date in significantly extending survival, with a low rate and duration of remission being identified in most trials. The challenge for both the health service and the pharmaceutical industry is to harness recent and future developments in scientific knowledge to the practical benefit of clinicians. Where cure is possible it should be vigorously pursued; where it is not, in this field above all others, clinicians have a duty of care. To achieve this it is necessary to abandon the therapeutic nihilism that has characterized the attitudes of clinicians towards this disease in the past. It is time that such nihilism was replaced by a recognition of the challenges and the opportunities available to clinicians in enhancing the quantity and quality of life available to patients. The dictum of 'curing whenever possible but caring always' should be the future therapeutic philosophy used to guide clinicians in this important and rapidly changing therapeutic area.

Pyrazoloacridine (PZA) is an acridine derivative selected for clinical development because of broad pre-clinical antitumor activity and solid tumor selectivity. Phase I evaluations with PZA have demonstrated predictable toxicity and suggested clinical efficacy. A phase II trial in patients with previously untreated advanced pancreatic cancer was conducted.

PZA was administered at a dose of 750 mg/m2 intravenously over 3 hours every 21 days. Seventeen patients were treated receiving a total of 46 courses of PZA.

Of the 15 patients evaluable for response, no responses were observed (0% response rate, 95% confidence interval 0-22%). Major toxicities directly attributable to PZA included moderate neutropenia and mild neurotoxicity.

PZA at this dose and schedule of administration was inactive in patients with pancreatic carcinoma.

Nuclear DNA content and pathology are considered to be prognostically relevant in several solid tumors, but controversial findings have emerged in pancreatic carcinoma (PC). Histopathology and DNA ploidy were each correlated with survival in radically treated PC to ascertain the hierarchy of their prognostic significance.

DNA ploidy was assessed by flow cytometry (FC) in neoplastic tissue samples from 60 patients with PC who were followed until death. Representative neoplastic areas were obtained by microdissection from archival paraffin embedded material (excluding any carcinoma with a coefficient of variation of the G0/G1 peak higher than 8%). Histologic data and FC patterns were related to prognostic behavior using univariate multivariate statistical analysis.

Aneuploid cancers were detected in 39 of 60 patients. Univariate analysis showed that histologic grade, nuclear grade, and ploidy were significantly related to prognosis. On multivariate analysis, only histologic grade and DNA ploidy (diploid vs. aneuploid) were significant with significant interaction.

The prognostic value of pathology and ploidy was demonstrated in patients treated radically for PC. As in other tumors characterized by a short survival, the clinical usefulness of any prognostic parameters is somewhat limited. However, the significant relationship between prognosis and DNA ploidy might be of interest in a cost-benefit analysis for selecting patients in whom an attempt at radical surgical treatment or adjunctive chemotherapy may be justified.

Antisense oligonucleotides targeting p53 have been hailed as a potentially new technique for treating patients with cancer, and there have been encouraging reports of good patient tolerance in vivo and of antiproliferative effects in vitro. However, evidence is lacking that these oligonucleotides are acting via an antisense interaction to modulate p53 expression. We examined a phosphorothioate antisense oligonucleotide, directed against exon 10 of the TP53 gene, and a chimaeric phosphorothioate-phosphodiester oligonucleotide directed against the p53 translation initiation codon. Both failed to specifically suppress p53 protein production in a cell-free assay system or to have any effect on mutant p53 expression by human pancreatic cancer cell lines. Antiproliferative effects were apparent, especially with the phosphorothioate antisense oligonucleotide, but this was independent of the p53 status of the cells (mutant, wild-type or absent) and also occurred with the control (sense and randomised) oligonucleotides. The most dramatic antiproliferative effects were seen with the 'control' phosphorothioate oligonucleotides. These findings suggest that the antiproliferative effects of some antisense oligonucleotides may be unrelated to expression of the gene they have been designed to target.

Trends in death certification rates from pancreatic cancer over the period 1955-1989 were analyzed for 25 European countries (excluding the former Soviet Union and a few smaller countries). In 1985-1989, rates for males ranged between 5.3/100,000 (age-standardized world population) in Spain and 10.3/100,000 in Hungary and Czechoslovakia. Other high-mortality areas were located in Northern Europe (Finland, Iceland, Ireland, Denmark) and Central Europe (Austria, Poland, Germany), whilst mortality was lower in Southern Europe (Portugal, Greece). Between 1955 and 1989, mortality rates increased in all the countries considered, the change ranging between 6% in Scotland and 279% in Spain; the rises were higher in the Mediterranean and Eastern European countries than in Northern Europe. Among females, Nordic countries such as Iceland, Sweden and Denmark had the highest mortality rates in 1985-1989 (over 6/100,000) and, as for males, Southern Europe (Spain, Portugal, Greece) appeared as a low-mortality area (around 3/100,000). During the 1955-1989 period, upward trends were observed in all the countries studied, with the highest increase in Greece, Italy, Bulgaria, Poland and Spain. A negative correlation was observed between the percent change in mortality rates between 1955-1959 and 1985-1989 and the rate in 1955-1959 among both males (r = -0.95, p < 0.001) and females (r = -0.81, p < 0.001). Thus, a systematic levelling of rates was observed in most countries, with the exception of the UK and some Nordic countries, whose rates were already high in the late 1950s. Tobacco smoking and dietary factors could account for some of the generalized upward trends. Improved diagnostic and death certification of the disease might also partially explain the observed figures.