[Recommendations of the Spanish Pancreatic Club on the diagnosis and treatment of chronic pancreatitis: part 2 (treatment)]. / Recomendaciones del Club Español Pancreático para el diagnóstico y tratamiento de la pancreatitis crónica: parte 2 (tratamiento).

Chronic pancreatitis (CP) is a complex disease with a wide spectrum of clinical manifestations ranging from asymptomatic disease to disabling forms or serious complications. The management of CP frequently differs among geographical areas and even among centers. These differences are due to the scarcity of high-quality studies and clinical practice guidelines that focus on the diagnosis and treatment of this disease. The aim of the Spanish Pancreatic Club was to create evidence-based recommendations for the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. These experts were selected on the basis of their clinical and research experience in CP. A list of questions was drawn up and each question was then reviewed by two panelists. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. Levels of evidence were based on the classification of the Oxford Centre for Evidence-Based Medicine. In the second part of the consensus process, recommendations were established for the management of pain, pseudocysts, biliary and duodenal stenosis, pancreatic fistula and ascites, left portal hypertension, diabetes mellitus, exocrine pancreatic insufficiency, and nutritional support in CP.

[Recommendations of the Spanish Pancreatic Club on the diagnosis and treatment of chronic pancreatitis: part 1 (diagnosis)]. / Recomendaciones del Club Español Pancreático para el diagnóstico y tratamiento de la pancreatitis crónica: parte 1 (diagnóstico).

Chronic pancreatitis (CP) is a relatively uncommon, complex and highly heterogeneous disease. There is no clear pattern applicable to the initial stages of CP, which hampers its early diagnosis. Some of the complications of CP, especially chronic pain, can be difficult to manage. There is wide variation in the diagnosis and treatment of CP and its complications among centers and health professionals. The Spanish Pancreatic Club has developed a consensus document on the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. A list of questions was drawn up. Each question was reviewed by two experts. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. The first part of the consensus document focusses on the diagnosis of CP and its complications.

Relationships of hepatic and pancreatic biomarkers with the cholestatic syndrome and tumor stage in pancreatic cancer.

We analyzed relationships of hepatic and pancreatic biomarkers with the cholestatic syndrome and tumor stage in exocrine pancreatic cancer (N = 183). Information on laboratory tests and on signs and symptoms was obtained from medical records and patient interviews. Bilirubin, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT) and alkaline phosphatase were lower in tumor stage IV. The association was due to the relationship between cholestatic syndrome and earlier presentation of patients. There was no association between hepatic biomarkers and stage when adjusting by cholestatic syndrome. Relationships of hepatic and pancreatic biomarkers with pancreatic symptoms and tumor stage must be controlled in "-omics" and other studies using biomarkers.

Pancreatic cancer risk and levels of trace elements.

BACKGROUND AND AIMS: Knowledge on the aetiology of exocrine pancreatic cancer (EPC) is scant. The best established risk factor for EPC is tobacco smoking. Among other carcinogens, tobacco contains cadmium, a metal previously associated with an increased risk of EPC. This study evaluated the association between concentrations of trace elements in toenails and EPC risk. METHODS: The study included 118 EPC cases and 399 hospital controls from eastern Spain. Levels of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. OR and 95% CI, adjusted for potential confounders, were calculated using logistic regression. RESULTS: Significantly increased risks of EPC were observed among subjects whose concentrations of cadmium (OR 3.58, 95% CI 1.86 to 6.88; p(trend)=5×10(-6)), arsenic (OR 2.02, 95% CI 1.08 to 3.78; p(trend)=0.009) and lead (OR 6.26, 95% CI 2.71 to 14.47; p(trend)=3×10(-5)) were in the highest quartile. High concentrations of selenium (OR 0.05, 95% CI 0.02 to 0.15; p(trend)=8×10(-11)) and nickel (OR 0.27, 95% CI 0.12 to 0.59; p(trend)=2×10(-4)) were inversely associated with the risk of EPC. CONCLUSION: Novel associations are reported of lead, nickel and selenium toenail concentrations with pancreas cancer risk. Furthermore, the results confirm previous associations with cadmium and arsenic. These novel findings, if replicated in independent studies, would point to an important role of trace elements in pancreatic carcinogenesis.

Clinical validity of detecting K-ras mutations for the diagnosis of exocrine pancreatic cancer: a prospective study in a clinically-relevant spectrum of patients.

The diagnostic utility of detecting K-ras mutations for the diagnosis of exocrine pancreatic cancer (EPC) has not been properly studied, and few reports have analysed a clinically relevant spectrum of patients. The objective was to evaluate the clinical validity of detecting K-ras mutations in the diagnosis of EPC in a large sample of clinically relevant patients. We prospectively identified 374 patients in whom one of the following diagnoses was suspected at hospital admission: EPC, chronic pancreatitis, pancreatic cysts, and cancer of the extrahepatic biliary system. Mutations in the K-ras oncogene were analysed by PCR and artificial RFLP in 212 patients. The sensitivity and specificity of the K-ras mutational status for the diagnosis of EPC were 77.7% (95% CI: 69.2-84.8) and 78.0% (68.1-86.0), respectively. The diagnostic accuracy was hardly modified by sex and age. In patients with either mutated K-ras or CEA > 5 ng/ml, the sensitivity and specificity were 81.0% (72.9-87.6) and 62.6% (72.9-87.6), respectively. In patients with mutated K-ras and CEA > 5 ng/ml the sensitivity was markedly reduced. In comparisons with a variety of non-EPC patient groups sensitivity and specificity were both always greater than 75%. In this clinically relevant sample of patients the sensitivity and specificity of K-ras mutations were not sufficiently high for independent diagnostic use. However, it seems premature to rule out the utility of K-ras analysis in conjunction with other genetic and 'omics' technologies.

Lifetime history of alcohol consumption and K-ras mutations in pancreatic ductal adenocarcinoma.

BACKGROUND: In pancreatic ductal adenocarcinoma (PDA), evidence on the etiopathogenic role of alcohol consumption in the occurrence of K-ras mutations is scant, and the role of alcohol in pancreatic carcinogenesis is not well established. We analyzed the relation between lifetime consumption of alcohol and mutations in codon 12 of the K-ras oncogene in patients with PDA. METHODS: Incident cases of PDA were prospectively identified and interviewed face-to-face during hospital admission about lifetime alcohol consumption and other lifestyle factors. Logistic regression was used to compare PDA cases (N = 107) with mutated and wild-type K-ras tumors (case-case study). RESULTS: Mutated cases were moderate or heavy drinkers more frequently than wild-type cases: the odds ratio adjusted by age, sex, smoking, and history of pancreatitis (ORa) was 3.18 (95% confidence interval: 1.02-9.93; P = 0.046). Total grams of alcohol and years of consumption were higher in mutated than in wild-type cases: the ORa for lifetime alcohol consumption over 507,499 g was 3.35 (95% CI: 0.81-13.88); and for more than 40 years of alcohol consumption it was 4.47 (95% CI: 1.05-19.02). Age at onset of alcohol consumption and years of abstinence were also associated with the presence of K-ras mutations. There were no significant differences in alcohol dependency. CONCLUSIONS: Alcohol consumption is weakly associated with an increased risk of having a K-ras mutated PDA. To confirm or to refute the hypothesis that ethanol, acetaldehyde or other alcohol-related substances might influence the acquisition or persistence of K-ras mutations in the pancreatic epithelium, large and unselected studies are warranted.

[Treatment of pain in chronic pancreatitis]. / Tratamiento del dolor en la pancreatitis crónica.

Abdominal pain is the most frequent symptom in patients with chronic pancreatitis. Between 70 and 90% of patients experience pain at some point in the course of their disease. In patients with alcoholic pancreatitis, pain is usually experienced at disease onset. Two distinct forms of idiopathic chronic pancreatitis can be distinguished: in early-onset (juvenile) idiopathic chronic pancreatitis, pain occurs initially, while in late-onset (senile) idiopathic chronic pancreatitis, pain is delayed or may even be absent. According to several authors, between 27 and 67% of patients require surgery due to lack of response to medical treatment. Pain may reoccur in more than 30% of patients who have undergone surgery and consequently, reintervention is not uncommon. Several treatment options are currently available: medical, endoscopic and surgical. The most appropriate treatment for each patient should be chosen on an individualized basis.

Management of painful chronic pancreatitis with single-dose radiotherapy.

OBJECTIVES: Some patients with chronic pancreatitis present recurrent flare-ups of pancreatitis and/or unrelenting pain. Current management is mostly limited to analgesics and surgery. We reasoned that anti-inflammatory radiotherapy, which has proven useful to alleviate other painful inflammatory painful disorders, might prove valuable for severely symptomatic patients with chronic pancreatitis. METHODS: We prospectively studied the efficacy of single-dose anti-inflammatory radiotherapy in 15 consecutive patients with chronic pancreatitis who fulfilled the following criteria: either two flare-ups of pancreatitis in the previous 6 months and/or continuous pain for more than 3 months. Treatment consisted of a single radiation dose of 8 Gy to the pancreas. Exocrine function (fecal elastase), endocrine function (c peptide), quality of life (EuroQol questionnaire), and clinical outcome were assessed before and after radiation. Response was defined as no further pain or flare-ups of pancreatitis. RESULTS: During follow-up (median: 39 months; range: 4-72 months), 12 patients had no further pain or flare-ups. One patient required a second radiation dose 1 year after the initial treatment, but he has remained well ever since (50 months). Two other patients did not respond to radiotherapy. After radiotherapy either exocrine or endocrine pancreatic function, or both, deteriorated in three patients. Patients who responded to treatment (13/15) gained 4-20 kg in body weight during follow-up (median 4 kg) and EuroQol improved significantly from 0.58 to 0.86 (P<0.001). CONCLUSIONS: Radiotherapy for severe symptomatic chronic pancreatitis appears to be a useful and effective therapeutic choice that could potentially substitute for or delay surgery.

Lifetime history of tobacco consumption and K-ras mutations in exocrine pancreatic cancer.

OBJECTIVES: We analyzed the relation between mutations in codon 12 of the K-ras oncogene and lifetime consumption of tobacco in patients with exocrine pancreatic cancer (EPC). METHODS: Incident cases of EPC were prospectively identified and interviewed during hospital admission about smoking and other factors. Exact logistic regression was used to compare EPC cases (N = 107) with and without K-ras mutations (case-case study). RESULTS: Mutated cases were nonsignificantly less likely to have been smokers than wild-type cases: the odds ratio adjusted by age and sex was 0.54 (95% confidence interval, 0.10-2.69; P = 0.613). With respect to never smokers, adjusted odds ratios for former and current smokers were 0.79 and 0.36, respectively (P = 0.193). Pack-years smoked, years of smoking, and cigarettes smoked per year also tended to be higher in nonmutated than in mutated cases. Neither age at onset of smoking nor the time between quitting and diagnosis were associated with K-ras. CONCLUSIONS: Tobacco does not play a major part in the acquisition of K-ras mutations in the pancreatic epithelium. Although both smoking and K-ras mutations have important roles in the etiopathogenesis of EPC, the 2 processes may act independently.

Food and nutrient intakes and K-ras mutations in exocrine pancreatic cancer.

BACKGROUND: No studies have investigated the relation between K-ras mutations and dietary factors in exocrine pancreatic cancer (EPC), and fewer than 10 studies have done so in other neoplasms. PATIENTS AND METHODS: Incident cases of EPC were prospectively identified, and interviewed face-to-face during hospital admission. Food and nutrient intakes were measured with a food frequency questionnaire. Logistic regression was used to compare EPC cases (n = 107) with and without K-ras mutations (case-case study). RESULTS: K-ras mutations were more common among daily consumers of milk and other dairy products than among non-daily consumers: the odds ratio adjusted by total energy, age, sex, smoking, alcohol and coffee consumption (ORa) was 5.1 (95% CI 1.1 to 24.5, p = 0.040). For all dairy products, including butter, the ORa for the medium and upper tertiles of intake were 5.4 and 11.6, respectively (p for trend = 0.023). The ORa for regular coffee drinkers further adjusted by dairy consumption was 4.7 (95% CI 1.1 to 20.7, p = 0.043). K-ras mutated cases reported a lower intake of vitamin E (ORa = 0.2, p for trend = 0.036), polyunsaturated fats and omega 3 fatty acids (ORa = 0.2; p for trend <0.03). CONCLUSIONS: Results support the hypothesis that in EPC exposure to specific dietary components or contaminants may influence the occurrence or persistence of K-ras mutations.

Common variable immunodeficiency: association between memory B cells and lung diseases.

BACKGROUND: Malabsorption syndrome often develops in patients with common variable immunodeficiency (CVID). Why structural damages appear in some CVID patients and not in others is not fully understood. Memory B cells (MBs) are responsible for the production of specific antibodies, and their defects have previously been related to autoimmune, granulomatous, and lymphoproliferative complications of CVID. The objective of this study was to ascertain whether a relationship exists between MB defects and the clinical outcome of respiratory and intestinal involvement in these patients. METHODS: Forty-one CVID patients were grouped as follows, according to the quantification of peripheral MBs: the MB2 group (n = 7) included patients with normal MBs; the MB1 group (n = 16) included patients with low switched MBs; and the MB0 group (n = 18) included patients with absent/low MBs. The clinical outcome of respiratory and intestinal involvement of patients was then compared among the three groups. RESULTS: In the MB0 group, chronic lung disease (ie, bronchiectasis and diminished FVC and/or FEV1) developed in 50% of patients vs 13% in the MB1 group and 0% in the MB2 group (p < 0.05). In the MB0 group, malabsorption syndrome or chronic noninfectious diarrhea developed in 50% of patients vs 19% in the MB1 group and 0% in the MB2 group (p < 0.05). No differences were found among the three groups for age at onset of symptoms, delay in diagnosis/treatment, months of follow-up/treatment, and prediagnostic serum IgG concentration. CONCLUSIONS: Alterations in MB count appear to be associated with a severe clinical outcome of respiratory and intestinal involvement in CVID. The MB count could be a useful laboratory parameter for orienting the prognosis and management of CVID patients.

Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage.

INTRODUCTION: The need to detect pancreatic cancer at earlier stages is undisputed. We recorded the signs and symptoms of patients presenting with exocrine pancreatic cancer and evaluated their association with clinical characteristics such as tumour site and disease stage. PATIENTS AND METHODS: All patients (n = 185) with exocrine pancreatic cancer newly diagnosed at five general hospitals in Eastern Spain were prospectively recruited over 5 years. Symptoms were elicited through personal interviews and signs were recorded by the attending physician on admission. RESULTS: At diagnosis, one third of tumours of the pancreas head were in stage I and another third in stage IV. None of the tumours of the body and tail were in stage I, and over 80% were in stage IV (p < 0.001) . At presentation, the most frequent symptoms were asthenia (86%), anorexia (85%), weight-loss (85%), abdominal pain (79%), and choluria (59%). Cholestatic symptoms were more common in tumours affecting only the pancreatic head (p < 0.001) . There was a clear trend toward more localized tumours with increasing numbers of cholestatic signs (p < 0.001) . Asthenia, anorexia and weight-loss were unrelated to stage. An increased symptom-to-diagnosis interval was associated with more advanced stage (p = 0.048). CONCLUSIONS: Proper attention to signs and symptoms, especially cholestasis, may help identify patients with pancreatic cancer at an earlier stage. Results also provide a current picture of the semiology of pancreatic cancer which could be of use in studies on the potential of proteomic tests in the early detection of this neoplasm.

Hydrogen breath test with low-dose rice flour for assessment of exocrine pancreatic insufficiency.

OBJECTIVES: The hydrogen (H2) breath test is widely used in the assessment of carbohydrate malabsorption. Severe exocrine pancreatic insufficiency markedly diminishes pancreatic amylase production and results in malabsorption of complex carbohydrates. Thus, the H2 breath test with low-dose rice flour starch was tested to determine its value in detecting exocrine pancreatic insufficiency by comparison with a direct measurement of pancreatic function. METHODS: Ten patients with clinically suspected pancreatic insufficiency confirmed with a duodenal perfusion technique and measurement of trypsin and lipase output after cerulein stimulation were included. An H2-rice flour breath test was performed by orally administering 30 g of rice flour. End-alveolar breath samples were obtained before rice load and at 30-minute intervals thereafter for the next 5 hours. RESULTS: The results are expressed as median (percentile 25-75). Patients included 8 men and 2 women with moderate to severe exocrine pancreatic insufficiency due to chronic pancreatitis, pancreatectomy, or cystic fibrosis. Stimulated duodenal output of lipase and trypsin was abnormally low in all patients (median release, 1.7; range, 0.5-4.5 and 0.8, range, 0.1-11.3 KU/h, respectively). Basal H2 excretion was 9 ppm (range, 7-17) and delta increase over basal H2 excretion was 4 ppm (range, 1-6). Correlation between H2-rice breath test and basal or stimulated duodenal output of lipase and trypsin was not significant. CONCLUSION: In exocrine pancreatic insufficiency, an oral load of 30 g rice flour slightly raises H2 excretion in breath. This increase is not useful for detecting pancreatic insufficiency due to poor sensitivity and because it is influenced by extrapancreatic factors such as small bowel bacterial overgrowth.

[Cystic fibrosis in adults: study of 111 patients]. / Fibrosis quística del adulto: estudio de 111 pacientes.

BACKGROUND: Our goal was to establish the clinical and genetic characteristics of patients diagnosed with adult-onset cystic fibrosis (CF). PATIENTS AND METHOD: This was a retrospective observational descriptive comparative study of CF patients according to their age at the time of diagnosis. All adult patients (> 16 years old) attended in our CF Unit until November 2001 were included in the study. Those patients diagnosed of CF at their childhood (< 16 years old) were categorized as Group A patients, and those diagnosed in adulthood (>= 16 years old) were categorized as group B patients. Anthropometric parameters, respiratory and digestive clinical abnormalities, chest and abdominal radiological exams, sputum bacteriology, respiratory function and genetic tests were evaluated. Statistical analysis between groups was performed by comparing chi square test for qualitative values and the Student t test for quantitative values. RESULTS: One hundred and eleven patients (60 women, mean age 28, range 16-69 years) out of a total sample of 245 (45.3%) patients attended at the CF unit were enrolled in the study. Group A included 61 patients (32 women; mean age 23) and group B included 50 patients (28 women; mean age 32). The comparative study between both groups showed that patients in group B were older, had a higher weight and less incidence of initial digestive abnormalities, pancreatic insufficiency, malnutrition, hepatic disease, chronic bronchial colonization by Pseudomonas aeruginosa, admissions, lung transplantation and deaths due to CF. On the contrary, these patients had a higher incidence of pancreatitis, allergic bronchopulmonary aspergillosis at diagnosis and better respiratory function test parameters. The sweat test was negative in 4 patients of group B and 1 of group A. The genetic study showed 31 different CF mutations, from which only 10 were observed in group B. CONCLUSIONS: CF can also be diagnosed in adult age. Patients diagnosed in adulthood have less digestive abnormalities, better lung function and different genetic mutations. The sweat test can be negative or undetermined. These patients also display a better prognosis.

Effect of short-term octreotide therapy and total parenteral nutrition on the development of biliary sludge and lithiasis.

BACKGROUND/AIMS: Both total parenteral nutrition and long-term octreotide treatment (> 2 months) may induce biliary sludge and lithiasis. However, the lithogenic capacity of the combination of the two treatments in the short-term is unknown. This study was undertaken to evaluate the lithogenic capacity of short-term octreotide treatment (< 1 month) in patients with acute pancreatitis who are also receiving total parenteral nutrition, and to determine the evolution of patients who develop biliary sludge and/or lithiasis. METHODOLOGY: Thirty patients with acute pancreatitis were studied (21 males, 9 females; average age: 38). All patients received total parenteral nutrition and analgesics. In a double-blind random manner, 15 patients were treated with a continuous subcutaneous administration of octreotide (200 micrograms/8 h) and a further 15 patients received placebo. Biliary sludge and/or lithiasis were examined by ultrasonography. An echographic examination of the gallbladder was performed every seven days while the patients were in hospital. They were followed up every month, when another ultrasound of the gallbladder was carried out. RESULTS: Sixteen patients (53%) developed sludge: ten (67%) from the octreotide group and six (33%) from the placebo group (P = 0.29). Two of the patients from the octreotide group had microlithiasis (P = 0.34) and a cholecystectomy was required. In the other 14 patients, sludge had disappeared by the time of the check-up performed one month after discharge. CONCLUSIONS: Short-term octreotide treatment does not increase the risk of developing biliary sludge and/or lithiasis in patients also receiving total parenteral nutrition. Biliary sludge formed during total parenteral nutrition and short-term octreotide therapy may disappear when patients begin oral intake. Therefore, preventive measures are not required.