The Liverpool duodenum-and spleen-preserving near-total pancreatectomy can provide long-term pain relief in patients with end-stage chronic pancreatitis.

PURPOSE: Total pancreatectomy may improve symptoms in patients with severe end-stage chronic pancreatitis. This might be achieved whilst preserving both the duodenum- and spleen-(DPSPTP). Mature clinical outcomes of this approach are presented. METHODS: Single-centre prospective cohort study performed between September 1996 and May 2016. Demographic, clinical details, pain scores and employment status were prospectively recorded during clinic attendance. RESULTS: Fifty-one patients (33 men, 18 women) with a median (interquartile range) age of 40.8 (35.3-49.4) years, a median weight of 69.8 (61.0-81.5) Kg and a median body mass index of 23.8 (21.5-27.8), underwent intended duodenum-and spleen-preserving near-total pancreatectomy for end-stage chronic pancreatitis. Aetiology was excess alcohol in 25, idiopathic (no mutation) in 15, idiopathic (SPINK-1/CFTR mutations) in two, hereditary (PRSS1 mutation) in seven and one each post-necrotising pancreatitis and obstructive pancreatic duct divisum in 1. The main indication for surgery was severe pain. Findings included parenchymal calcification in 79% and ductal calculi in 24%, a dilated main pancreatic duct in 57% and a dilated main bile duct in 17%, major vascular involvement in 27% and pancreato-peritoneal fistula in 2%. Postoperative complications occurred in 20 patients with two deaths. Median pain scores were 8 (7-8) preoperatively and 3 (0.25-5.75) at 5 years (p = 0.013). Opiate analgesic use was significantly reduced postoperatively (p = 0.048). Following surgery, 22 (63%) of 38 patients of working age re-entered employment compared with 12 (33%) working preoperatively (p = 0.016). CONCLUSION: Duodenum-and spleen-preserving near-total pancreatectomy provided long-term relief in adult patients with intractable chronic pancreatitis pain, with improved employment prospects.

False positive carbohydrate antigen 19-9 (CA19-9) results due to a low-molecular weight interference in an apparently healthy male.

BACKGROUND: We investigated the presence of interference in a patient who had an elevated CA19-9 concentration using the ADVIA Centaur but results within reference limits with ROCHE Modular Analytics E170 and Brahms KRYPTOR analysers. METHODS: We performed repeat analyses using the same (ADVIA Centaur) and alternate immunossays (Roche Modular Analytics E170 and Brahms KRYPTOR) on the patient's sample and investigated for known interferences. To determine the nature of the interference, we measured CA19-9 on the ADVIA Centaur after dilution experiments and after incubation with non-immune animal sera and in heterophilic blocking tubes (HBT). We also undertook polyethylene glycol precipitation, lectin inhibition experiments and gel filtration chromatography. RESULTS: A curvilinear response to dilution was observed with the ADVIA Centaur. Other known interferences were excluded. Treatment with HBT or non-immune animal sera did not give clinically different results from untreated samples. There was only 0.59% recovery after PEG precipitation in the sample from the case patient. Lectin reduced the assay signal in four patient samples (recovery=1.9-14.1%) but not in the case patient (recovery=106.2%). Gel filtration studies suggested the presence of a low molecular weight (approximately 100 kDa) interference in the case patient's serum. CONCLUSIONS: We report a novel mode of interference and show a non-CA19-9, low molecular-weight interference affecting the ADVIA Centaur CA19-9 immunoassay.

Carbohydrate antigen 19.9 accurately selects patients for laparoscopic assessment to determine resectability of pancreatic malignancy.

BACKGROUND: Laparoscopy with laparoscopic ultrasonography (L-LUS) may be useful in the selection of patients for surgery to resect peripancreatic malignancy in addition to contrast-enhanced computed tomography (CE-CT). The present prospective study assessed the strategy of using carbohydrate antigen 19.9 (CA19.9) levels to select patients for L-LUS. METHODS: Patients with suspected peripancreatic malignancy that appeared resectable on CE-CT were selected for immediate surgery if CA19.9 was low (up to 150 kU/l, or up to 300 kU/l if serum bilirubin was above 35 micromol/l), or to L-LUS if CA19.9 was high (over 150 kU/l, or over 300 kU/l if serum bilirubin was above 35 micromol/l). Data were assessed to determine the clinical utility of this strategy. RESULTS: A total of 94 patients went straight to surgery, of whom 65 proved resectable: 63 of 80 with a low CA19.9 level but only two of 14 with a high CA19.9 level and gastric outlet obstruction. From 55 patients with high CA19.9 levels, L-LUS correctly identified 26 of 31 resectable tumours and eight of 24 unresectable tumours. CONCLUSION: Using CA19.9 levels to help select patients with pancreatic malignancy for immediate surgery or L-LUS for further assessment of resectability effectively increased resection rates and reduced unnecessary laparotomies.

Familial pancreatic cancer: a review and latest advances.

Familial Pancreatic Cancer (FPC) is the autosomal dominant inheritance of a genetic predisposition to pancreatic ductal adenocarcinoma, penetrance is assumed to be high but not complete. It was first described in 1987 and since then many families have been identified, but the candidate disease gene remains elusive and the very existence of the syndrome is sometimes questioned. FPC identifies a target group for secondary screening. As well as being potentially life saving for the subjects, screening offers researchers the opportunity to elucidate the early pathogenesis of pancreatic cancer. The scientific incentive for screening should not blind us to the challenges facing clinicians in managing high risk patients. Early surgical treatment may dramatically improve the five year survival for pancreatic cancer, but this must be balanced against the risks of false positives, where healthy individuals are subjected to the mortality and morbidity of major pancreatic surgery.

Mechanisms of acinar cell injury in acute pancreatitis.

Acute pancreatitis has many causes, all leading to a common pathway of changes within the pancreatic acinar cell. Key amongst these changes is premature intracellular activation of digestive enzymes but this is also accompanied by the appearance of cytosolic vacuoles, co-localization of digestive and lysosomal enzymes, activation of NF-kappaB, and release of pro-inflammatory cytokines. The exact mechanism responsible for enzyme activation remains the subject of much research effort and not a little debate, however it is clear that all of these changes are triggered by an abnormal, sustained rise in cytosolic calcium concentration, which is itself dependent both on release of calcium from endoplasmic reticulum stores and uptake from the extracellular milieu. Activated enzymes are directly damaging to the acinar cell themselves, but recruitment of circulating neutrophils leads to further cellular damage. Cytokines and neutrophil activation are also responsible for the systemic inflammatory response typically seen in severe acute pancreatitis.

Surgery in the treatment of acute pancreatitis--minimal access pancreatic necrosectomy.

Between 5% and 10% of patients with acute pancreatitis will develop infected pancreatic necrosis. Traditional open surgery for this condition carries a mortality rate of up to 50%, and therefore a number of less invasive techniques have been developed, including radiological drainage and a minimal access retroperitoneal approach. No randomised controlled trials have been published which compare these techniques. Indications for minimal access surgery are the same as for open surgery, i.e. infected pancreatic necrosis or failure to improve with extensive sterile necrosis. Access is obtained to the pancreatic necrosis via the left loin and necrosectomy performed using an operating nephroscope, and this often requires several procedures to remove all necrotic tissue. The cavity is continuously irrigated on the ward in between procedures. The results of this approach are encouraging, with less systemic upset to the patient, a lower incidence of post-operative organ failure when compared with open surgery, and a reduced requirement for ITU support. There is also a trend towards a lower mortality rate, although this does not reach statistical significance on the data published so far. Current evidence suggests that a minimal access approach to pancreatic necrosis is feasible, well tolerated and beneficial for the patient when compared with open surgery.

Early and late complications after pancreatic necrosectomy.

BACKGROUND: Surgery for pancreatic necrosis is associated with a high morbidity and mortality. The aim of this study was to review the incidence of early and late complications after pancreatic necrosectomy in a large contemporary series of patients. METHODS: The clinical outcomes of 88 patients who underwent pancreatic necrosectomy between 1997 and 2003 were reviewed. RESULTS: The median age was 55.5 (range, 18-85) years, 54 (61%) were males, 68 (77%) had primary pancreatic infection, 71 (81%) had >50% necrosis, and the median admission Acute Physiology and Chronic Health Evaluation score was 9 (range, 1-21). Median time to surgery was 31 (range, 1-161) days; 47 patients underwent minimally invasive necrosectomy and 41 open necrosectomy; 81 (92%) of patients had complications postoperatively, and 25 (28%) died. Multiorgan failure (odds ratio = 3.4, P = .05) and hemorrhage (odds ratio = 6.1, P = .03) were the only independent predictors of mortality. During a median follow-up of 28.9 months, 39 (62%) of 63 surviving patients had one or more late complications: biliary stricture in 4 (6%), pseudocyst in 5 (8%), pancreatic fistula in 8 (13%), gastrointestinal fistula in 1 (2%), delayed collections in 3 (5%), and incisional hernia in 1 (2%); intervention was required in 10 (16%) patients. Sixteen (25%) of 63 surviving patients developed exocrine insufficiency, and 19 (33%) of 58 without prior diabetes mellitus developed endocrine insufficiency. CONCLUSIONS: Almost all patients undergoing necrosectomy developed significant early or late complications or both. Multiorgan failure and postoperative hemorrhage were independent predictors of mortality. Long-term follow-up was important because 62% developed complications, and 16% of those with complications required surgical or endoscopic intervention.

Review article: chemotherapy for pancreatic cancer.

Pancreatic cancer is a common, highly lethal disease that is rising in incidence. Chemotherapy based on 5-fluorouracil (5-FU) has been shown to prolong survival in advanced pancreatic cancer. Gemcitabine improves major symptoms and survival outcomes compared with bolus 5-FU. Many novel small molecules are being widely and actively researched. These compounds are based on classical mechanisms of action as well as biological therapies targeting novel cellular survival pathways, and include fluoropyrimidines, nucleoside cytidine analogues, platinum analogues, topoisomerase-inhibitors, antimicrotubule agents, proteasome inhibitors, vitamin D analogues, arachidonic acid pathway inhibitors, histone deacytylator inhibitors, farnesyltransferase inhibitors and epidermal growth factor receptor therapies. Adjuvant chemotherapy has also demonstrated the best survival outcomes following resection compared to other adjuvant or neo-adjuvant strategies such as radiation-based treatments. These benefits are superimposed on the dramatic increase in resectability rates and reduction in post-operative mortality achieved by centralisation of treatment in high-volume speciality centres. Newer 'small-molecule' drugs as well as the latest 'large-molecule' biological agents hold considerable promise for the future. Real advances are anticipated over the next five years but are dependent on large randomised controlled trials for success.

Adjuvant therapy in pancreatic cancer: historical and current perspectives.

The results from pancreatic ductal adenocarcinoma appear to be improving with increased resection rates and reduced postoperative mortality reported by specialist pancreatic cancer teams. Developments with medical oncological treatments have been difficult, however, due to the fundamentally aggressive biological nature of pancreatic cancer and its resistance to chemotherapy coupled with a relative dearth of randomised controlled trials. The European Study Group for Pancreatic Cancer (ESPAC)-1 trial recruited nearly 600 patients and is the largest trial in pancreatic cancer. The results demonstrated that the current best adjuvant treatment is chemotherapy using bolus 5-fluorouracil with folinic acid. The median survival of patients randomly assigned to chemoradiotherapy was 15.5 months and is comparable with many other studies, but the median survival in the chemotherapy arm was 19.7 months and is as good or superior to multimodality treatments including intra-operative radiotherapy, adjuvant chemoradiotherapy and neo-adjuvant therapies. The use of adjuvant 5-fluorouracil with folinic acid may be supplanted by gemcitabine but requires confirmation by ongoing clinical trials, notably ESPAC-3, which plans to recruit 990 patients from Europe, Canada and Australasia. Major trials such as ESPAC-1 and ESPAC-3 have set new standards for the development of adjuvant treatment and it is now clear that such treatment in this field has the potential to significantly improve both patient survival and quality of life after curative resection.

[Adjuvant and additive therapy for cancer of the pancreas]. / Adjuvante und additive Therapie beim Pankreaskarzinom.

Recent advances have been made in the treatment of pancreas cancer. Specialized pancreas centres have reported an increasing rate of resections with reduced postoperative mortality. On account of the highly aggressive nature of pancreas cancer, there is a great challenge in identifying effective therapy concepts for advanced stages of the cancer as well as for the development of resection-associated measures. As large-scale, randomised, controlled studies are lacking, the additive therapy concepts after resection do not have a sufficiently scientific basis. The ESPAC-1 study, which included 600 patients, surpassed all previous studies on adjuvant therapy for pancreas cancer. This study has shown,for example, that the most promising adjuvant chemotherapy with 5-fluorouracil and folic acid leads to an equal if not better result than the multimodal regimen. This regimen can be superseded with the use of Gemcitabine, which will be evaluated in the ESPAC-3 study that includes 990 patients from various European countries including Germany, as well as from Canada and Australia. Participation in the large, phase-3 study therefore plays a key role in the continued development of the management of pancreas cancer.

Surgery for midgut carcinoid.

Many clinicians prefer to avoid surgery in patients with carcinoid neoplasia, because of its slow growth and relatively favourable prognosis. Nevertheless, the commonest cause of death in patients with carcinoid is advanced metastatic disease, and both clinical and epidemiological data indicate that the more effectively the disease is ablated, the more long-lasting the benefit. Multidisciplinary management of patients with carcinoid must consider inherited risk, possible multiple carcinoids and/or synchronous non-carcinoid cancer, and the use of a range of investigations that also evaluate the 10% of patients with carcinoid syndrome with or without valvular heart disease. Although primary size is correlated with the presence of nodal with or without liver metastases, carcinoid tumours <1 cm in diameter may be metastatic at presentation, particularly those arising within the small intestine. In the jejunum and ileum, resection of all sizes of carcinoid with local and regional nodes is preferred, to prevent nodal dissemination causing mesenteric ischaemia with or without infarction. Resection of nodal metastases should be undertaken in those with persistent or recurrent nodal disease if possible. Appendiceal and right colonic carcinoids are most effectively treated by right hemicolectomy with local and regional nodal clearance, as for adenocarcinoma. However, for most appendiceal carcinoids which are <1 cm in diameter and non-invasive, appendicectomy alone is sufficient. For appendiceal carcinoids 1-2 cm in diameter, histopathological assessment helps to determine the need for hemicolectomy. Liver resection has been followed by prolonged 5 year survival in several series and is recommended in appropriate patients to attempt cure or to debulk metastatic disease. Liver transplantation has had only qualified success in highly selected patients without extra-hepatic disease in whom other therapies have failed.