The Spanish Pancreatic Club recommendations for the diagnosis and treatment of chronic pancreatitis: part 1 (diagnosis).

Chronic pancreatitis (CP) is a relatively uncommon, complex and heterogeneous disease. The absence of a gold standard applicable to the initial phases of CP makes its early diagnosis difficult. Some of its complications, particularly chronic pain, can be difficult to manage. There is much variability in the diagnosis and treatment of CP and its complications amongst centers and professionals. The Spanish Pancreatic Club has developed a consensus on the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts on this disease. A list of questions was drafted, and two experts reviewed each question. Then, a draft was produced and shared with the entire panel of experts and discussed in a face-to-face meeting. This first part of the consensus addresses the diagnosis of CP and its complications.

The Spanish Pancreatic Club's recommendations for the diagnosis and treatment of chronic pancreatitis: part 2 (treatment).

Chronic pancreatitis (CP) is a complex disease with a wide range of clinical manifestations. This range comprises from asymptomatic patients to patients with disabling symptoms or complications. The management of CP is frequently different between geographic areas and even medical centers. This is due to the paucity of high quality studies and clinical practice guidelines regarding its diagnosis and treatment. The aim of the Spanish Pancreatic Club was to give current evidence-based recommendations for the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts on this disease. These experts were selected according to clinical and research experience in CP. A list of questions was made and two experts reviewed each question. A draft was later produced and discussed with the entire panel of experts in a face-to-face meeting. The level of evidence was based on the ratings given by the Oxford Centre for Evidence-Based Medicine. In the second part of the consensus, recommendations were given regarding the management of pain, pseudocysts, duodenal and biliary stenosis, pancreatic fistula and ascites, left portal hypertension, diabetes mellitus, exocrine pancreatic insufficiency, and nutritional support in CP.

Clinical usefulness of K-ras gene mutation detection and cytology in pancreatic juice in the diagnosis and screening of pancreatic cancer.

BACKGROUND: The significance of K-ras codon 12 mutation in pancreatic juice is still unclear. Although considerable controversy surrounds this question, the diagnostic utility of K-ras in patients with clinical suspicion of pancreatic cancer (PC) and in PC-risk patients remains unknown. OBJECTIVE: To study prospectively the utility of the K-ras gene mutation and cytology in the diagnosis and screening of PC, and to assess its contribution to clinical decision making. METHODS: Pancreatic juice samples obtained from 90 patients were evaluated prospectively. Group I (n = 40) comprised patients with clinical suspicion of PC; group II (n = 50) comprised 49 patients with chronic pancreatitis and one patient proceeding from a PC family screening. The K-ras mutation was detected by means of artificial restriction fragment length polymorphisms (RFLP) in DNA after polymerase chain reaction (PCR) amplification. RESULTS: In group I, of those patients with a definitive diagnosis of PC, malignant cells were found in 27% and K-ras mutation in 44%. In five cases, molecular analysis contributed to diagnosis (4/11 with negative cytology and 1/2 with insufficient cytological material). K-ras mutation revealed an early tumour in one patient, and was the only sample available for diagnosis in another. In group II, the K-ras gene mutation was detected in 8/49 patients (16%) with chronic pancreatitis, one of whom developed PC (2%). CONCLUSIONS: K-ras mutation analysis of pancreatic juice may complement cytological evaluation in the diagnosis of PC, in spite of its limited contribution to clinical decision making. The presence of K-ras mutation in chronic pancreatitis classifies a subgroup of PC-risk patients who should be evaluated carefully by long-term follow-up.

Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding.

BACKGROUND: After an episode of acute bleeding from esophageal varices, patients are at high risk for recurrent bleeding and death. We compared two treatments to prevent recurrent bleeding--endoscopic ligation and combined medical therapy with nadolol and isosorbide mononitrate. METHODS: We randomly assigned 144 patients with cirrhosis who were hospitalized with esophageal variceal bleeding to receive treatment with endoscopic ligation (72 patients) or the combined medical therapy (72 patients). Sessions of ligation were repeated every two to three weeks until the varices were eradicated. The initial dose of nadolol was 80 mg orally once daily, with adjustment according to the resting heart rate; isosorbide mononitrate was given in increasing doses, beginning at 20 mg once a day at bed time and rising over the course of one week to 40 mg orally twice a day, unless side effects occurred. The primary end points were recurrent bleeding, complications, and death. RESULTS: The median follow-up period was 21 months. A total of 35 patients in the ligation group and 24 in the medication group had recurrent bleeding. The probability of recurrence was lower in the medication group, both for all episodes related to portal hypertension (P=0.04) and for recurrent variceal bleeding (P=0.04). There were major complications in nine patients treated with ligation (seven had bleeding esophageal ulcers and two had aspiration pneumonia) and two treated with medication (both had bradycardia and dyspnea) (P=0.05). Thirty patients in the ligation group died, as did 23 patients in the medication group (P=0.52). The probability of recurrent bleeding was lower for patients with a hemodynamic response to therapy, defined as a decrease in the hepatic venous pressure gradient of more than 20 percent from the base-line value or to less than 12 mm Hg (18 percent, vs. 54 percent in patients with no hemodynamic response at one year; P<0.001), and the probability of survival was higher (94 percent vs. 78 percent at one year, P=0.02). CONCLUSIONS: Combined therapy with nadolol and isosorbide mononitrate is more effective than endoscopic ligation for the prevention of recurrent bleeding and is associated with a lower rate of major complications. A hemodynamic response to treatment is associated with a better long-term prognosis.

Somatostatin treatment and risk stratification by continuous portal pressure monitoring during acute variceal bleeding.

BACKGROUND AND AIMS: During acute variceal bleeding, several factors may lead to elevations of hepatic venous pressure gradient (HVPG), which may precipitate further hemorrhage. Whether somatostatin can suppress these increments is unknown. This study monitored somatostatin effects on HVPG during acute bleeding and assessed whether the changes affect outcome. METHODS: In 40 patients with acute variceal bleeding treated with sclerotherapy, a catheter was placed into a main hepatic vein for 24-hour serial measurements of HVPG. After baseline measurements, patients received somatostatin (N = 25) or placebo (N = 15) under double blind conditions. RESULTS: Somatostatin but not placebo produced a sustained decrease in HVPG (from 20.7 +/- 3.7 mm Hg to 17.7 +/- 2.7, P < 0.01). In patients receiving placebo, HVPG increased after a test meal (P = 0.018) and after blood transfusion (P = 0.034). Somatostatin completely prevented these increments. HVPG decreased significantly only in patients without further bleeding. One of 27 patients with HVPG <20 mm Hg at baseline or decreased >10% rebled vs. 9 of 13 who had neither of these 2 criteria (P < 0.0001). Both criteria had independent prognostic value for further bleeding. CONCLUSIONS: During acute variceal bleeding, somatostatin produces a significant and sustained decrease in HVPG and prevents secondary elevations. Monitoring HVPG may stratify further bleeding risk and discriminate treatment response.

Prospective evaluation of the contribution of K-ras mutational analysis and CA 19.9 measurement to cytological diagnosis in patients with clinical suspicion of pancreatic cancer.

The aim of this study was to prospectively evaluate the diagnostic contribution of the detection of K-ras mutation and measurement of serum CA 19.9 concentrations to cytological diagnosis in patients with clinical suspicion of pancreatic cancer. These patients had either the presence or absence of a pancreatic mass as determined by imaging procedures. A total of 156 consecutive patients with clinical suspicion of pancreatic cancer or for confirmation and follow-up of their chronic pancreatitis disease were included: 84 patients presenting a pancreatic mass (group 1) and 72 patients without a pancreatic mass (group 2). K-ras mutations were detected by a restriction fragment length polymorphism/polymerase chain reaction (RFLP/PCR) method and CA 19.9 by an immunoluminometric assay. When a pancreatic mass was present, cytology offered a high sensitivity, but with a significant number of inconclusive results and K-ras mutational analysis offered a highly specific test. In the absence of a pancreatic mass, CA 19.9 (cut-off 100 U/ml) increased the sensitivity of the diagnosis by cytology and K-ras mutational analysis did not add significant information. Thus both tests contribute to the clinical decision process when pancreatic cancer is clinically suspected and the cytological report is not conclusive.

Survival of cancer of the pancreas. Bases for new strategies in diagnosis and therapy.

OBJECTIVE: The ominous prognosis of pancreatic carcinoma (PC) has led to a nihilistic attitude among physicians, and to the need to develop better tools for diagnosis, staging and treatment. The aim of this study was to analyze a series of patients with PC in order to determine stage-related survival, and to try to improve diagnostic and therapeutic strategies. METHODS: This was a retrospective study of 167 patients diagnosed from 1987 to 1993. The diagnosis was based on cytological pathology findings or on a clinical course compatible with PC. TNM stage and survival were calculated. We also analyzed age, sex, time elapsed until diagnosis, diagnostic tests, size and location, cytologic pathology confirmation, number of patients undergoing surgery, and procedures used. RESULTS: Age: 67 +/- 12 years, 82 men and 85 women. Time elapsed until diagnosis: 3 +/- 15.7 months. Pathologic diagnosis: 74.8%. LOCATION: head 75%, body 13.9%, tail 7.2%, diffuse 2.4%, not reported 1.2%. Size: 4.6 +/- 2 cm. TNM staging: stage I 13%; stage II 25%; stage III 20%; stage IV 42%. Stage-related survival: stage I 14 months; stage II 6 months; stage III 4 months; stage IV 1 month. Total survival: 3 months. Surgery was done in 66.5% and resection in 10%; curative surgery in 6.5%; bypass in 81% and diagnostic laparotomy in 9%. In 55% of the patients surgery revealed a higher stage of disease than had been diagnosed preoperatively. Postoperative mortality was 18%. Survival at 1 and 5 years after curative surgery was 80% and 20%, respectively. CONCLUSIONS: Diagnosis was made at a late stage in many patients. Few patients were candidates for radical surgery. Early diagnosis, preoperative staging and postoperative management should be improved in these patients, and surgery should be associated with complementary chemotherapy and/or radiotherapy.

Cáncer de páncreas: supervivencia. Bases para una nueva estrategia diagnóstica y terapéutica / Survival of cancer of the pancreas. Bases for new strategies in diagnosis and therapy

El mal pronóstico del cáncer de páncreas (CP) motiva con frecuencia una actitud nihilista y consecuentemente un diagnóstico, estadiaje y tratamiento insuficientes. OBJETIVO: analizar la supervivencia de una serie de pacientes con CP para tratar de mejorar la estrategia diagnóstica y terapéutica. PACIENTES: estudio retrospectivo de 167 pacientes diagnosticados entre 1987-1993 con confirmación anatomo_ patológica o evolución clínica compatible con CR Se evaluó: edad, sexo, intervalo hasta el diagnóstico, pruebas diagnósticas, tamaño y localización, diagnóstico anatomopatológico, número de intervenciones, tipo de cirugía realizada, estadio TNM y supervivencia. RESULTADOS: edad: 67 ñ 12 años, 82 varones y 85 mujeres. Intervalo hasta el diagnóstico: 3 ñ 15,7 meses. Diagnóstico anatomopatológico: 74,8 por ciento. Localización: cabeza, 75 por ciento; cuerpo, 13,9 por ciento; cola, 7,2 por ciento; difuso, 2,4 por ciento, y no consta, 1,2 por ciento. Tamaño: 4,6 ñ 2 cm. Estadiaje: 13 por ciento, estadio 1; 25 por ciento, estadio U; 20 por ciento, estadio III, y 42 por ciento, estadio IV. Supervivencia: estadio 1, 14 meses; estadio H, 6 meses; estadio 111, 4 meses, y estadio IV, 1 mes. Supervivencia global: 3 meses. Indice de operabilidad. del 66,5 por ciento y de resecabilidad del 10 por ciento; cirugía curativa, 5,5 por ciento; derivativa, 81 por ciento, y laparotomía exploradora, en un 9 por ciento.Tras cirugía un 55 por ciento sufrió un cambio de su estadio preoperatorio por otro más avanzado. Mortalidad postoperatoria: 18 por ciento. Supervivencia postcirugía curativa: 80 por ciento al año y 20 por ciento a los 5 años. CONCLUSIONES: la mayoría de pacientes fueron diagnosticados tardíamente y consecuentemente pocos pacientes fueron candidatos a cirugía radical. En este contexto deben mejorarse el diagnóstico precoz, el estadiaje preoperatorio y los resultados de la cirugía que debe asociarse a la quimioterapia y/o radioterapia complementaria (AU)

A highly sensitive method for K-ras mutation detection is useful in diagnosis of gastrointestinal cancer.

Detection of molecular features such as K-ras mutations has been used to evaluate potential tumour markers in a wide variety of clinical samples. Here we have applied a recently developed highly sensitive method for detection of K-ras codon 12 mutations to colorectal and pancreatic cancer diagnosis. We analysed 67 faecal samples from patients undergoing diagnostic colonoscopy under suspicion of colorectal cancer. PCR products were obtained in 62 of 67 (93%) faecal samples. Mutations were detected in exfoliated cells in 6 of 22 (27%) of the adenomas and in 6 of 11 (55%) of adenocarcinomas. No false positives were observed. Agreement between faecal samples and corresponding tissues was 100% for adenocarcinomas and 65% for adenomas. Mutations were also analysed in 61 pancreatic fine-needle aspirates. Mutations were detected in 36 of 45 (80%) of the pancreatic aspirates diagnosed as pancreatic cancer without false positives. Our findings suggest that, when colorectal cancer is suspected, detection of K-ras codon 12 mutations in faecal samples using this new method is specific for colorectal tumours. Additionally, this technique is a good alternative for evaluation of pancreatic masses.

[Accuracy of imaging techniques and tumor markers in the diagnosis of pancreatic cancer]. / Precisión diagnóstica de los métodos de imagen y de los marcadores tumorales séricos en el cáncer de páncreas.

OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of: a) three imaging techniques: ultrasonography (US), computed tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP), and b) the serum tumor markers CEA, CA 19-9 and CA 125, in the diagnosis of pancreatic cancer. PATIENTS AND METHODS: A total of 137 patients were prospectively evaluated. Pancreatic cancer was diagnosed in 25 patients; chronic pancreatitis in 24; acute pancreatitis in 22; extrapancreatic malignancies in 24, and benign digestive disease in 42. The reference interval for each marker was determined in 36 healthy volunteers. Diagnostic accuracy was determined using receiver operating characteristic (ROC) curves. Each diagnostic test was used in order: a) to diagnose pancreatic cancer when the disease was clinically suspected, and b) to differentiate between pancreatic cancer and chronic pancreatitis. RESULTS: CT (0.976-0.888) and US (0.857) diagnostic accuracy resulted greater than the best serum tumor marker CA 19-9 (0.755-0.786) (p = NS), in both diagnostic conditions. To obtain a diagnostic specificity of 90% in pancreatic cancer, the CA 19-9 cutoff level should increase up to 3 and 7.5 folds being in this case better than CEA and CA 125 (p < 0.05). CONCLUSIONS: CT scan offers the greatest accuracy in the diagnosis of PC. Among the tumor markers, CA 19-9 offers the best accuracy in the diagnosis of pancreatic cancer.

Somatostatin alone or combined with emergency sclerotherapy in the treatment of acute esophageal variceal bleeding: a prospective randomized trial.

Recent trials have shown that somatostatin (SMT) is as effective as sclerotherapy in the treatment of acute variceal bleeding and that the combination of both treatments is more effective than sclerotherapy alone. To assess whether the addition of sclerotherapy improves the efficacy of SMT alone, all patients admitted to our unit with gastrointestinal bleeding and with suspected cirrhosis received a continuous infusion of SMT (250 micrograms/h). Endoscopy was performed between 1 and 5 hours later, and patients with esophageal variceal bleeding were randomized to receive or not to receive sclerotherapy. In both groups, SMT infusion was continued for 5 days. Fifty patient admissions were allocated to each group. Therapeutic failure occurred in 21 cases of the SMT group and in 7 cases of the combined-therapy group (P =.002). Failure to control the acute episode occurred in 24% vs. 8% (P =.03) and early rebleeding in 24% vs. 7% (P =.03), respectively. Transfusional requirements were significantly higher in the SMT group, while the incidence of complications was lower (8% vs. 24%; P =.029). In the multivariate analysis, the presence of shock at admission and active bleeding during endoscopy were the variables that better predicted the failure of therapy with SMT alone. Mortality at 6 weeks was similar. These data demonstrate that the addition of sclerotherapy significantly improves the efficacy of SMT alone for the treatment of acute variceal bleeding, although it also increases the rate of complications. Patients with shock and those with active bleeding are more likely to benefit from this combined therapy.

K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significance.

PURPOSE: Previous studies have demonstrated the presence of K-ras mutations in the plasma of patients with pancreatic carcinoma. However, the diagnostic utility and the prognostic significance of this finding have never been addressed. PATIENTS AND METHODS: Forty-four consecutive patients with histologically confirmed primary pancreatic ductal adenocarcinoma were included. A control group of 37 patients with chronic pancreatitis, 10 patients with other tumors of the pancreatic area, nine patients with acute pancreatitis, and four healthy volunteers was also included. Plasma DNA was isolated and K-ras codon-12 mutations were analyzed by means of restriction fragment length polymorphism-polymerase chain reaction and single-strand conformation polymorphism techniques. Patients were followed up to establish their clinical outcome. RESULTS: The mutant-type K-ras gene was found in plasma DNA samples of 12 (27%) of 44 patients with pancreatic ductal adenocarcinoma; this finding was related to the tumor stage (P = .05), mainly in the presence of distant metastases (P = .02). In addition, K-ras mutations were detected in the plasma DNA of two (5%) of 37 patients with chronic pancreatitis. In the subset of patients with pancreatic masses, the sensitivity and specificity of plasma K-ras analysis for pancreatic adenocarcinoma were 27% and 100%, respectively. Finally, pancreatic carcinoma patients with the mutant-type K-ras gene in plasma DNA exhibited a shorter survival time than patients with the wild-type gene (P<.005), and plasma K-ras mutations were identified as the only independent prognostic factor (odds ratio, 1.51; 95% confidence interval, 1.02 to 2.23). CONCLUSION: Plasma K-ras analysis is a highly specific, low-sensitivity approach that has diagnostic and prognostic clinical implications in patients with pancreatic carcinoma.

K-ras gene mutations in the diagnosis of fine-needle aspirates of pancreatic masses: prospective study using two techniques with different detection limits.

Detection of K-ras mutations may be useful in the evaluation of pancreatic cancer. The aim of this study was to assess, in a prospective design, the diagnostic utility of K-ras mutation analysis in 62 consecutive fine-needle aspirates of pancreatic masses, using two PCR-based techniques-standard and enriched-with detection limits of a mutant allele in the presence of 10(2) or 10(3) wild-type alleles, respectively. Cytology alone offered a diagnostic sensitivity of 75%. The enriched higher sensitivity detection technique, in combination with cytology, offered a diagnostic sensitivity of 91% without false positives. The molecular analysis would have contributed to diagnosis in an additional 14 cases of pancreatic cancer. The standard technique contributed to diagnosis in an additional 9 cases. These results strongly support the use of the enriched method of detecting K-ras mutations as a complement to cytology in the evaluation of pancreatic masses.

[Tuberculous pancreatic abscess: differential diagnosis and favorable response to medical treatment]. / Absceso tuberculoso pancreático: diagnóstico diferencial y respuesta favorable al tratamiento médico.

Pancreatic tuberculosis is rare and may present differential diagnostic problems, specially with cancer of the pancreas. An immunocompetent patient with a pancreatic tuberculous abscess whose clinical manifestations were epigastric pain and a toxic syndrome of one month of evolution is presented. A cystic mass was detected on computerized axial tomography in the tail of the pancreas suggestive of irresectable carcinoma because of vascular invasion with negative percutaneous cytologic puncture for malignant cells. The patient was surgically treated with no histologic confirmation of malignancy. A second laparotomy was performed at 6 months since spontaneous size reduction, external pancreatic fistula with miliary peritoneal dissemination and biopsy compatible with tuberculous granulomas was found. Staining for resistant acid-alcohol bacilli were always negative. Medical treatment achieved complete disappearance of the pancreatic tumor in one year.

Prevalence of thyroid autoantibodies is not increased in blood donors with hepatitis C virus infection.

Serum autoimmune reactions are found in many patients with hepatitis C. A high prevalence of thyroid dysfunction and antithyroid antibodies in patients with chronic hepatitis C was recently reported. We have compared the prevalence of thyroid dysfunction and antithyroid peroxidase antibodies in blood donors with hepatitis C virus (HCV) infection (study group) and in seronegative anti-HCV donors (control group). One hundred and ninety-two blood donors were studied: 96 were anti-HCV positive by ELISA 2 (48 males and 48 females; age 48 +/- 12.9 years, mean +/- SD), and 96 were HCV seronegative (55 males and 41 females; age 37 +/- 14.8 years). In all patients, serum TSH (0.25-4.2 mU/l) and fT4 (9-23 pmol/l) were measured by immunochemiluminiscent assays and antithyroid peroxidase antibodies (normal < 100 U/ml) by RIA. In all anti-HCV positive donors, hepatitis C viremia was tested using the nested polymerase chain reaction. Thyroid dysfunction was found in three females (3.1%) in the anti-HCV positive group (three cases of hypothyroidism), and in four (4.1%) anti-HCV negative blood donors (three cases of hypothyroidism, two females and one male; one case of hyperthyroidism, a female), (p = NS). Antithyroid peroxidase antibody titers were above normal values in 5 (5.2%) anti-HCV positive individuals and in eight (8.3%) anti-HCV negative blood donors (p = NS). These results do not show an increase prevalence of thyroid dysfunction and antithyroid peroxidase antibodies in blood donors with HCV infection when compared with a control group.

[Portasystemic shunt in the treatment of gastropathy caused by portal hypertension]. / Derivación portosistémica en el tratamiento de la gastropatía por hipertensión portal.

Gastropathy by portal hypertension constitutes the second cause of digestive hemorrhage in these patients following esophagogastric varices. Beta-blocker drugs seem efficient in treatment as occasionally does therapeutic endoscopy. The case of a patient with chronic liver disease with upper digestive hemorrhage is presented. The patient did not respond to medical treatment with beta-blockers nor to endoscopy (thermic and sclerosant). Portocaval anastomosis was performed with no posterior hemorrhagic relapse. The use of shunt surgery has been suggested in this pathology given the rarity of its presentation in patients with this type of operation. The satisfactory evolution of the patient seems to confirm this hypothesis.