Distal pancreatectomy for benign and malignant tumours is the second most common surgical procedure on the pancreas. Postoperative pancreatic fistulas (POPF) represent the most significant clinical complication, causing prolongation of hospital stay and the need for additional diagnostic and therapeutic procedures. Although various techniques for preventing POPF have been evaluated, to date, there is no available technique that ensures closure of the pancreatic remnant.
DISCOVER will aim to investigate differences in the postoperative course after a distal pancreatectomy comparing the standard surgical technique with an alternative technique that provides additional coverage of the pancreatic remnant by the falciform ligament. The primary endpoint of this trial will be the rate of POPF. As secondary endpoints, incidence of postoperative morbidity and mortality, length of hospital stay, and quality of life will be assessed.
DISCOVER is a single-centre, randomised, controlled surgical trial. For statistical analysis, a binary logistic regression model will be used. With a level of significance of 5% and a power of 80%, a sample size of 75 patients per group has been identified as necessary.
The findings of this trial will help to evaluate the usefulness of the coverage procedure at reducing the rate of POPF. The results could influence the standard procedure for remnant closure after distal pancreatectomy.
Clinical trials register (DRKS-ID: DRKS00000546)
Coverage procedure; Distal pancreatectomy; Falciform ligament; Pancreatic fistula
AIM: To evaluate quality of life (QoL) after curative liver resection and identify variables associated with decreased QoL.
METHODS: From October 2001 to July 2004, 323 patients underwent liver resection. At 3-36 mo after discharge, 188 patients were disease free. QoL was assessed using the Short Form (SF)-12 Health Survey with mental and physical component scales (SF-12 MCS and PCS), supplemented with generic questions concerning pain and liver-specific items.
RESULTS: Sixty-eight percent (128/188) returned the questionnaire, which was completed in 75% (96/128) of cases. Median SF-12 PCS and MCS were 46.7 (interquartile range: 34.2-53.9) and 54.1 (42.8-58.2). Fifty percent were pain free with a median symptom score of 1.75 (1.38-2.13). PCS was higher after major hepatectomy [57% (55/96)] compared to minor resection (P = 0.0049), which represented an improved QoL. QoL was not affected by sex but by age compared to the general German population. MCS was higher after liver surgery for metastatic disease [55.9 (47.5-58.8)] compared to primary carcinoma [49.6 (36.5-55.1)] and benign disease [49.2 (37.7-56.3)] (P = 0.0317). There was no correlation between length of postoperative period and QoL. Pain, deficiencies in everyday life and a high symptom score significantly decreased MCS and PCS.
CONCLUSION: Most patients were only marginally affected even after major liver resection; however, minor complications were associated with decreased SF-12 MCS and PCS and need careful attention.
Quality of life; Liver resection
Transforming growth factors βs (TGF‐βs) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF‐βs modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild‐type (FVB−/−) and transgenic mice that are heterozygous (FVB+/−) for expression of a dominant negative type II TGF‐β receptor.
After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed.
The normal mouse pancreas was devoid of inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild‐type mice resulted in 6‐ and 36‐fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/− mice exhibited minimal alterations in response to caerulein with attenuated neutrophil–macrophage infiltrates. Moreover, acini from FVB+/− mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased.
Our findings indicate that a functional TGF‐β signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.
Tumor-exosomes being reported to suppress or promote a cancer-directed immune response, we used exosomes of the rat pancreatic adenocarcinoma BSp73ASML (ASML) to evaluate, whether and which steps in immune response induction can be affected by tumor-exosomes and how the impaired responsiveness can be circumvented.
ASML-exosomes bind to and are taken up by all leukocyte subpopulations in vivo and in vitro, uptake by CD11b+ leukocytes exceeding that by T and B cells. ASML-exosomes affect leukocyte proliferation via reduced CD44v6 up-regulation and lck, ZAP70 and ERK1,2 phosphorylation, which can be compensated by dendritic cells (DC). ASML-exosomes do not support Treg. Yet, impaired activation of anti-apoptotic signals is accompanied by slightly increased apoptosis susceptibility. IgM secretion is unaffected; NK and CTL activity are strengthened, ASML-exosomes co-operating with DC in CTL activation. ASML-exosomes transiently interfere with leukocyte migration by occupying migration-promoting receptors CD44, CD49d, CD62L and CD54 during binding/internalization.
ASML-exosomes might well serve as adjuvant in immunotherapy as they support leukocyte effector functions and have only a minor impact on leukocyte activation, which can be overridden by DC. However, exosome-induced modulation of immune cells relies, at least in part, on exosome uptake and message transfer. This implies that depending on the individual tumor's exosome composition, exosomes may distinctly affect the immune system. Nonetheless, whether immunotherapy can profit from using tumor-exosomes as adjuvant can easily be settled beforehand in vitro.
Tumor-exosomes; T cell activation; CTL; NK; Apoptosis; Leukocyte migration
The Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) were published in 2007 as the world’s first guidelines for acute cholangitis and cholecystitis. The diagnostic criteria and severity assessment of acute cholecystitis have since been widely used all over the world. A validation study of TG07 has shown that the diagnostic criteria for acute cholecystitis are highly reliable but that the definition of definite diagnosis is ambiguous. In addition, considerable new evidence referring to acute cholecystitis as well as evaluations of TG07 have been published. Consequently, we organized the Tokyo Guidelines Revision Committee to evaluate TG07, recognize new evidence, and conduct a multi-center analysis to revise the guidelines (TG13).
Methods and materials
We retrospectively analyzed 451 patients with acute cholecystitis from multiple tertiary care centers in Japan. All 451 patients were first evaluated using the criteria in TG07. The “gold standard” for acute cholecystitis in this study was a diagnosis by pathology. The validity of TG07 diagnostic criteria was investigated by comparing clinical with pathological diagnosis.
Of 451 patients evaluated, a total of 227 patients were given a diagnosis of acute cholecystitis by pathological examination (prevalence 50.3 %). TG07 criteria provided a definite diagnosis of acute cholecystitis in 224 patients. The sensitivity of TG07 diagnostic criteria for acute cholecystitis was 92.1 %, and the specificity was 93.3 %. Based on the preliminary results, new diagnostic criteria for acute cholecystitis were proposed. Using the new criteria, the sensitivity of definite diagnosis was 91.2 %, and the specificity was 96.9 %. The accuracy rate was improved from 92.7 to 94.0 %. In regard to severity grading among 227 patients, 111 patients were classified as Mild (Grade I), 104 as Moderate (Grade II), and 12 as Severe (Grade III).
The proposed new diagnostic criteria achieved better performance than the diagnostic criteria in TG07. Therefore, the proposed criteria have been adopted as new diagnostic criteria for acute cholecystitis and are referred to as the 2013 Tokyo Guidelines (TG13). Regarding severity assessment, no new evidence was found to suggest that the criteria in TG07 needed major adjustment. As a result, TG07 severity assessment criteria have been adopted in TG13 with minor changes.
Acute cholecystitis; Murphy’s sign; Diagnostic criteria; Severity assessment; Guidelines
TRAIL selectively kills cancer cells while bispecific antibody EpCAMxCD3 guides effector lymphocytes to cancer cells. Arming of ex vivo constructed TRAIL-lymphocytes with EpCAMxCD3 enhances contact time and affinity between lymphocytes and tumor cells and enforces tumor elimination. This boosts endogenous immune responses and augments the effect of cytotoxic tumor therapy.
bispecific antibodies; apoptosis; granzyme/perforin; cancer stem cells; gene-immunotherapy
The Tokyo Guidelines for the management of acute cholangitis and cholecystitis were published in 2007 (TG07) and have been widely cited in the world literature. Because of new information that has been published since 2007, we organized the Tokyo Guidelines Revision Committee to conduct a multicenter analysis to develop the updated Tokyo Guidelines (TG13).
We retrospectively analyzed 1,432 biliary disease cases where acute cholangitis was suspected. The cases were collected from multiple tertiary care centers in Japan. The ‘gold standard’ for acute cholangitis in this study was that one of the three following conditions was present: (1) purulent bile was observed; (2) clinical remission following bile duct drainage; or (3) remission was achieved by antibacterial therapy alone, in patients in whom the only site of infection was the biliary tree. Comparisons were made for the validity of each diagnostic criterion among TG13, TG07 and Charcot’s triad.
The major changes in diagnostic criteria of TG07 were re-arrangement of the diagnostic items and exclusion of abdominal pain from the diagnostic list. The sensitivity improved from 82.8 % (TG07) to 91.8 % (TG13). While the specificity was similar to TG07, the false positive rate in cases of acute cholecystitis was reduced from 15.5 to 5.9 %. The sensitivity of Charcot’s triad was only 26.4 % but the specificity was 95.6 %. However, the false positive rate in cases of acute cholecystitis was 11.9 % and not negligible. As for severity grading, Grade II (moderate) acute cholangitis is defined as being associated with any two of the significant prognostic factors which were derived from evidence presented recently in the literature. The factors chosen allow severity assessment to be performed soon after diagnosis of acute cholangitis.
TG13 present a new standard for the diagnosis, severity grading, and management of acute cholangitis.
Acute cholangitis; Biliary infection; Diagnostic criteria; Severity assessment; Charcot’s triad
Background. Several approaches have been proposed to pharmacologically ameliorate hepatic ischemia/reperfusion injury (IRI). This study was designed to evaluate the effects of a preconditioning oral nutritional supplement (pONS) containing glutamine, antioxidants, and green tea extract on hepatic warm IRI in pigs. Methods. pONS (70 g per serving, Fresenius Kabi, Germany) was dissolved in 250 mL tap water and given to pigs 24, 12, and 2 hrs before warm ischemia of the liver. A fourth dose was given 3 hrs after reperfusion. Controls were given the same amount of cellulose with the same volume of water. Two hours after the third dose of pONS, both the portal vein and the hepatic artery were clamped for 40 min. 0.5, 3, 6, and 8 hrs after reperfusion, heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), portal venous flow (PVF), hepatic arterial flow (HAF), bile flow, and transaminases were measured. Liver tissue was taken 8 hrs after reperfusion for histology and immunohistochemistry. Results. HR, MAP, CVP, HAF, and PVF were comparable between the two groups. pONS significantly increased bile flow 8 hrs after reperfusion. ALT and AST were significantly lower after pONS. Histology showed significantly more severe necrosis and neutrophil infiltration in controls. pONS significantly decreased the index of immunohistochemical expression for TNF-α, MPO, and cleaved caspase-3 (P < 0.001). Conclusion. Administration of pONS before and after tissue damage protects the liver from warm IRI via mechanisms including decreasing oxidative stress, lipid peroxidation, apoptosis, and necrosis.
Different suture techniques and various suture materials are in use to close midline incisions after primary laparotomy. The ISSAAC study aimed to assess the safety and efficacy of the new ultra-long-term absorbable, elastic monofilament suture material MonoMax® for abdominal wall closure.
This is a single-arm, multicentre prospective study that included 150 patients undergoing a primary elective midline incision. The control group consists of 141 patients from the INSECT study who received MonoPlus® or PDS® for abdominal wall closure. The incidences of burst abdomen and wound infection until the day of discharge were defined as the primary composite endpoints. The rate of incisional hernias 1 year after surgery, the length of postoperative hospital stay and safety parameters served as secondary endpoints. The study has been registered under www.clinicaltrials.gov [NCT005725079].
Eleven patients in the ISSAAC study [7.3%; 95% CI = (3.9; 13.1%)] experienced wound infection or burst abdomen until the day of discharge as compared to 16 [11.3%; 95% CI = (6.6; 17.8%)] patients in the INSECT control group (p = 0.31). The length of postoperative hospital stay was comparable in both study groups. One year after surgery, incisional hernias were observed in 21 ISSAAC patients (14.0%) in contrast to 30 hernias (21.3%) in the INSECT control group.
The ultra-long-term absorbable, elastic monofilament suture material MonoMax® is safe and efficient for abdominal wall closure.
Laparotomy; Abdominal hernia; Fascia; Suture materials; Humans
Hepatocellular carcinoma (HCC) is a molecular complex tumor with high intrinsic drug resistance. Recent evidence suggests an involvement of the tyrosine kinase pathway in the regulation of ATP-binding cassette protein (ABC-transport protein) mediated multidrug resistance in cancer cells. The aim of this study was to examine whether EGFR inhibition sensitizes HCCs to chemotherapy and to elucidate its mechanism.
Chemotherapeutic treatment induces multidrug resistance and significantly increases ABC-transport protein expression and function in a time- and dose-dependent manner in HCC cells. Furthermore, cytostatic treatment increases the mRNA expression of tyrosine kinases and induces the phosphorylation of ERK. EGF activation of the tyrosine kinase pathway up-regulated the ABC-transport protein mRNA expression and enhanced the survival of resistant HCC cells. Consistent with these effects, inhibition of the EGFR using siRNA decreased the ABC-transport protein mRNA expression and inhibited the proliferation of resistant cells. Additional treatment with Gefitinib, a clinically approved EGFR inhibitor, caused a dose-dependent reversal of resistance to conventional chemotherapy.
The present study demonstrates that the multidrug resistance of HCC is modulated through the EGF-activated tyrosine kinase cascade. Consequentially, the restoration of chemosensitivity by EGFR inhibition may lead towards new tailored therapies in patients with highly resistant tumors.
The utility of circulating angiogenic cytokines (CAC) as biomarkers in pancreatic cancer has not been clarified yet. We investigated the expression and prognostic associations of seven CAC in patients with pancreatic cancer.
Serum samples were collected preoperatively in patients undergoing surgery for localized pancreatic cancer (n = 74), metastatic pancreatic cancer (n = 24) or chronic pancreatitis (n = 20) and in healthy controls (n = 48). Quantitative enzyme-linked immunosorbent assays and multiplex protein arrays were used to determine circulating levels of VEGF, VEGFR-1, PlGF, PDGF-AA, PDGF-BB, Ang-1 and EGF. Multivariate analyses on cancer-specific survival were performed with a Cox proportional hazards model.
VEGF (p < 0.0001), PDGF-AA (p < 0.0001), Ang-1 (p = 0.002) and EGF (p < 0.0001) were differentially expressed in patients with pancreatic cancer compared to healthy controls. The presence of lymph node metastases was associated with increased levels of all CAC except for PlGF, whereas there were only minor associations of CAC with other clinicopathologic variables. The multivariate model including the entire angiogenic panel revealed high levels of circulating PDGF-AA (hazard ratio 4.58; 95% confidence interval 1.43 - 14.69) as predictor of poor cancer-specific survival, whereas high levels of PDGF-BB (0.15; 0.15 - 0.88), Ang-1 (0.30; 0.10 - 0.93) and VEGF (0.24; 0.09 - 0.57) were associated with a favorable prognosis.
Circulating levels of certain angiogenic cytokines correlate with patients' prognosis after resection for pancreatic cancer, if a panel of several CAC is considered simultaneously. These data should be considered in future studies evaluating angiogenic factors as prognostic biomarkers and therapeutic targets in patients with pancreatic cancer.
Pancreatic cancer is still associated with a poor prognosis and remains—as the fourth leading cause of cancer related mortality—a therapeutic challenge. Overall long-term survival is about 1–5%, and in only 10–20% of pancreatic cancer patients is potentially curative surgery possible, increasing five-year survival rates to approximately 20–25%. Pancreatic surgery is a technically challenging procedure and has significantly changed during the past decades with regard to technical aspects as well as perioperative care. Standardized resections can be carried out with low morbidity and mortality below 5% in high volume institutions. Furthermore, there is growing evidence that also more extended resections including multivisceral approaches, vessel reconstructions or surgery for tumor recurrence can be carried out safely with favorable outcomes. The impact of adjuvant treatment, especially chemotherapy, has increased dramatically within recent years, leading to significantly improved postoperative survival, making pancreatic cancer therapy an interdisciplinary approach to achieve best results.
pancreatic cancer; surgery; standard resection; extended approach
Circulating tumor cells (CTC) and disseminated tumor cells (DTC) are thought to be responsible for metastasis, so the detection of CTC may serve as individual prognostic factor in patients suffering from colorectal cancer. Therefore, a series of immunomagnetic enrichment methods for CTC have been developed using a variety of monoclonal antibodies against the Epithelial Cell Adhesion Molecule (EpCAM). However, it remains unclear whether all commercially available EpCAM antibodies show the same sensitivity and specificity. Furthermore, it remains unclear which method of sample preparation and cell extraction is most suitable for immunomagnetic enrichment and detection of CTC. In this study, we aimed to investigate whether the detection of CTC by a cytokeratin 20 reverse transcriptase-polymerase chain reaction (CK20 RT-PCR) may be influenced by the use of various Epithelial Cell Adhesion Molecule (EpCAM) antibodies for immunomagnetic isolation of CTC.
Using both EpCAM antibodies (mAb BerEP4 and mAb KS1/4) for immunomagnetic enrichment in blood samples of 39 patients with colorectal cancer we found heterogenous results in each patient with regard to tumor cell detection. In the tumor cell spiking experiments with whole blood samples the sensitivity of the CK 20 RT-PCR assay was higher using immunomagnetic beads coated with mAb KS1/4 compared to precoated mAb BerEP4 Dynabeads. Extraction of MNC fraction with Ficoll gradient centrifugation prior to immunomagnetic enrichment resulted in a higher sensitivity of the CK 20 RT-PCR assay.
We concluded that isolation and detection of CTC with immunomagnetic enrichment methods is critically dependent on the used EpCAM clone. Further studies with a larger number of patients should clarify if the enrichment protocol influences the prognostic value of the tumor cell detection protocol.
Background and aim
Chronic pancreatitis is characterised by severe abdominal neuropathic pain, perineural inflammatory cell infiltrations and intrapancreatic neural growth. Artemin was recently shown to eliminate neuropathic pain and reverse neurochemical damage after nerve injury. The role of artemin and its receptor GFRα3 was investigated in patients with chronic pancreatitis.
Expression of artemin and its receptor GFRα3 was studied in chronic pancreatitis (n = 66) and normal (n = 22) pancreatic tissues by quantitative reverse transcription‐polymerase chain reaction (QRT‐PCR) and western blot analysis. Artemin expression was correlated with pain and pathomorphological changes (inflammation, perineural inflammatory cell infiltration, neural alterations and fibrosis). Immunohistochemistry was used to localise artemin and GFRα3 in the tissues. To detect sources of artemin, primary human pancreatic stellate cells (hPSCs) were isolated and analysed by QRT‐PCR and immunocytology analysis.
In chronic pancreatitis, artemin and GFRα3 were significantly overexpressed and located in smooth muscle cells of arteries, Schwann cells and neural ganglia. Increased levels of artemin mRNA correlated with pain severity, inflammation, perineural inflammatory cell infiltration, neural density and hypertrophy. Furthermore, the severity of fibrosis was positively related with artemin expression and neural alterations. Activated hPSCs expressed low basal levels of artemin mRNA which were upregulated by exposure to transforming growth factor (TGF)β1.
Overexpression of artemin in chronic pancreatitis might function as a compensatory upregulation in order to repair neural damage incurred by ongoing pancreatic inflammation. Upregulation of TGFβ1 seems not only to increase pancreatic fibrosis but also to contribute to neural alteration by stimulating artemin expression in hPSCs. However, overexpression of endogenous artemin does not seem to be sufficient to prevent pain in chronic pancreatitis.
The clinical course of chronic pancreatitis is still unpredictable, which relates to the lack of the availability of a clinical classification. Therefore, patient populations cannot be compared, the course and the outcome of the disease remain undetermined in the individual patient, and treatment is not standardized.
To establish a clinical classification for chronic pancreatitis which is user friendly, transparent, relevant, prognosis- as well as treatment-related and offers a frame for future disease evaluation.
Diagnostic requirements will include one clinical criterion, in combination with well defined imaging or functional abnormalities.
A classification system consisting of three stages (A, B and C) is presented, which fulfils the above-mentioned criteria. Clinical criteria are: pain, recurrent attacks of pancreatitis, complications of chronic pancreatitis (e.g. bile duct stenosis), steatorrhea, and diabetes mellitus. Imaging criteria consist of ductal or parenchymal changes observed by ultrasonography, ERCP, CT, MRI, and/or endosonography.
A new classification of chronic pancreatitis, based on combination of clinical signs, morphology and function, is presented. It is easy to handle and an instrument to study and to compare the natural course, the prognosis and treatment of patients with chronic pancreatitis.
Pancreatic cancer is an extremely aggressive malignancy. Subjects are afflicted with a variety of disconcerting symptoms, including profound cachexia. Recent data indicate that the outcome of oncological patients suffering from cancer cachexia could be improved by parenteral nutrition and that parenteral nutrition results in an improvement of quality of life and in prolonged survival.
Currently, there is no recommendation of routine use of parenteral nutrition. Furthermore, there is no clear recommendation for 2nd line therapy (or higher) for pancreatic adenocarcinoma but often asked for.
PANUSCO is an open label, controlled, prospective, randomized, multicentre phase IIIb trial with two parallel arms. All patients will be treated with 5-fluorouracil, folinic acid and oxaliplatin on an outpatient basis at the study sites. Additionally, all patients will receive best supportive nutritional care (BSNC). In the experimental group BSNC will be expanded with parenteral nutrition (PN). In contrast, patients in the control group obtain solely BSNC. Parenteral nutrition will be applied overnight and at home by experienced medical staff.
A total of 120 patients are planned to be enrolled. Primary endpoint is the comparison of the treatment groups with respect to event-free survival (EFS), defined as the time from randomization till time to development of an event defined as either an impairment (change from baseline of at least ten points in EORTC QLQ-C30, functional domain total score) or withdrawal due to fulfilling the special defined stopping criteria for chemotherapy as well as for nutritional intervention (NI) or death from any cause (whichever occurs first).
The aim of this clinical trial is to evaluate whether parenteral nutrition in combination with defined 2nd line or higher chemotherapy has an impact on quality of life for patients suffering from pancreatic adenocarcinoma.
Current Controlled Trials ISRCTN60516908.
The aim of this article is to propose new criteria for the diagnosis and severity assessment of acute cholecystitis, based on a systematic review of the literature and a consensus of experts. A working group reviewed articles with regard to the diagnosis and treatment of acute cholecystitis and extracted the best current available evidence. In addition to the evidence and face-to-face discussions, domestic consensus meetings were held by the experts in order to assess the results. A provisional outcome statement regarding the diagnostic criteria and criteria for severity assessment was discussed and finalized during an International Consensus Meeting held in Tokyo 2006. Patients exhibiting one of the local signs of inflammation, such as Murphy’s sign, or a mass, pain or tenderness in the right upper quadrant, as well as one of the systemic signs of inflammation, such as fever, elevated white blood cell count, and elevated C-reactive protein level, are diagnosed as having acute cholecystitis. Patients in whom suspected clinical findings are confirmed by diagnostic imaging are also diagnosed with acute cholecystitis. The severity of acute cholecystitis is classified into three grades, mild (grade I), moderate (grade II), and severe (grade III). Grade I (mild acute cholecystitis) is defined as acute cholecystitis in a patient with no organ dysfunction and limited disease in the gallbladder, making cholecystectomy a low-risk procedure. Grade II (moderate acute cholecystitis) is associated with no organ dysfunction but there is extensive disease in the gallbladder, resulting in difficulty in safely performing a cholecystectomy. Grade II disease is usually characterized by an elevated white blood cell count; a palpable, tender mass in the right upper abdominal quadrant; disease duration of more than 72 h; and imaging studies indicating significant inflammatory changes in the gallbladder. Grade III (severe acute cholecystitis) is defined as acute cholecystitis with organ dysfunction.
Acute cholecystitis; Diagnosis; Severity of illness index; Guidelines; Infection
Because acute cholangitis sometimes rapidly progresses to a severe form accompanied by organ dysfunction, caused by the systemic inflammatory response syndrome (SIRS) and/or sepsis, prompt diagnosis and severity assessment are necessary for appropriate management, including intensive care with organ support and urgent biliary drainage in addition to medical treatment. However, because there have been no standard criteria for the diagnosis and severity assessment of acute cholangitis, practical clinical guidelines have never been established. The aim of this part of the Tokyo Guidelines is to propose new criteria for the diagnosis and severity assessment of acute cholangitis based on a systematic review of the literature and the consensus of experts reached at the International Consensus Meeting held in Tokyo 2006. Acute cholangitis can be diagnosed if the clinical manifestations of Charcot’s triad, i.e., fever and/or chills, abdominal pain (right upper quadrant or epigastric), and jaundice are present. When not all of the components of the triad are present, then a definite diagnosis can be made if laboratory data and imaging findings supporting the evidence of inflammation and biliary obstruction are obtained. The severity of acute cholangitis can be classified into three grades, mild (grade I), moderate (grade II), and severe (grade III), on the basis of two clinical factors, the onset of organ dysfunction and the response to the initial medical treatment. “Severe (grade III)” acute cholangitis is defined as acute cholangitis accompanied by at least one new-onset organ dysfunction. “Moderate (grade II)” acute cholangitis is defined as acute cholangitis that is unaccompanied by organ dysfunction, but that does not respond to the initial medical treatment, with the clinical manifestations and/or laboratory data not improved. “Mild (grade I)” acute cholangitis is defined as acute cholangitis that responds to the initial medical treatment, with the clinical findings improved.
Cholangitis; Diagnosis; Severity of illness index; Guidelines
Biliary decompression and drainage done in a timely manner is the cornerstone of acute cholangitis treatment. The mortality rate of acute cholangitis was extremely high when no interventional procedures, other than open drainage, were available. At present, endoscopic drainage is the procedure of first choice, in view of its safety and effectiveness. In patients with severe (grade III) disease, defined according to the severity assessment criteria in the Guidelines, biliary drainage should be done promptly with respiration management, while patients with moderate (grade II) disease also need to undergo drainage promptly with close monitoring of their responses to the primary care. For endoscopic drainage, endoscopic nasobiliary drainage (ENBD) or stent placement procedures are performed. Randomized controlled trials (RCTs) have reported no difference in the drainage effect of these two procedures, but case-series studies have indicated the frequent occurrence of hemorrhage associated with endoscopic sphincterotomy (EST), and complications such as pancreatitis. Although the usefulness of percutaneous transhepatic drainage is supported by the case-series studies, its lower success rate and higher complication rates makes it a second-option procedure.
Cholangitis; Endoscopic sphincterotomy; Biliary drainage; Percutaneous; Endoscopy; Endoscopic cholangiopancreatography; Guidelines
Cholecystectomy has been widely performed in the treatment of acute cholecystitis, and laparoscopic cholecystectomy has been increasingly adopted as the method of surgery over the past 15 years. Despite the success of laparoscopic cholecystectomy as an elective treatment for symptomatic gallstones, acute cholecystitis was initially considered a contraindication for laparoscopic cholecystectomy. The reasons for it being considered a contraindication were the technical difficulty of performing it in acute cholecystitis and the development of complications, including bile duct injury, bowel injury, and hepatic injury. However, laparoscopic cholecystectomy is now accepted as being safe for acute cholecystitis, when surgeons who are expert at the laparoscopic technique perform it. Laparoscopic cholecystectomy has been found to be superior to open cholecystectomy as a treatment for acute cholecystitis because of a lower incidence of complications, shorter length of postoperative hospital stay, quicker recuperation, and earlier return to work. However, laparoscopic cholecystectomy for acute cholecystitis has not become routine, because the timing and approach to the surgical management in patients with acute cholecystitis is still a matter of controversy. These Guidelines describe the timing of and the optimal surgical treatment of acute cholecystitis in a question-and-answer format.
Acute cholecystitis; Cholecystectomy; Laparoscopic cholecystectomy; Open surgery; Cholecystostomy; Guidelines
Dramatic weight loss is an often underestimated symptom in pancreatic cancer patients. Cachexia- defined as an unintended loss of stable weight exceeding 10% – is present in up to 80% of patients with cancer of the upper gastrointestinal tract, and has a significant influence on survival. The aim of the study was to show the multiple systemic effects of cachexia in pancreatic cancer patients, in terms of resection rate, effects on pulmonary function, amount of fat and muscle tissue, as well as changes in laboratory parameters.
In patients with pancreatic cancer, clinical appearance was documented, including the amount of weight loss. Laboratory parameters and lung-function tests were evaluated, and the thickness of muscle and fat tissue was measured with computed tomography scans. Statistical analysis, including multivariate analysis, was performed using SPSS software. Survival curves were calculated using Kaplan-Meier analysis and the log-rank test. To test for significant differences between the examined groups we used Student's t-test and the Mann-Whitney U test. Significance was defined as p < 0.05.
Of 198 patients with a ductal adenocarcinoma of the pancreas, 70% were suffering from weight loss when they presented for operation, and in 40% weight loss exceeded 10% of the stable weight. In patients with cachexia, metastases were diagnosed significantly more often (47% vs. 24%, P < 0.001), leading to a significantly reduced resection rate in these patients. Patients with cachexia had significantly reduced fat tissue amounts. Hence, dramatic weight loss in a patient with pancreatic cancer may be a hint of a more progressed or more aggressive tumour.
Pancreatic cancer patients with cachexia had a higher rate of more progressed tumour stages and a worse nutritional status. Furthermore, patients with cachexia had an impaired lung function and a reduction in fat tissue. Patients with pancreatic cancer and cachexia had significantly reduced survival. If weight loss exceeded 5% there was a significantly reduced resection rate to detect, but the changes were significantly more substantial if weight loss was 10% or more. We propose that a weight loss of 10% be defined as significant in pancreatic cancer.
While mortality following pancreaticoduodenectomy has progressively decreased over the last decade, its morbidity, especially the development of pancreatic fistula, has remained constant over the years. However, high volume centers and individual surgeons report a major decrease in the rate of post-operative pancreatic fistulas. Technical refinements are crucial to reduce, and if possible prevent, the development of pancreatic fistula. No uniformity of opinion exists as to the method of pancreatic anastomosis after resection and few reports provide a detailed description of the actual technique employed. This article illustrates step-by-step the technique of pancreaticojejunostomy as practiced by the authors. Apart from presenting our previously published experience, results from other centres around the world are also provided in this review article.
Pancreaticojejunostomy; Pancreatic reconstruction; Pancreaticoduodenectomy; Pancreatic head resection; Pancreatic fistula
The periampullary region gives rise to two main subtypes of adenocarcinoma that show either pancreatobiliary or intestinal differentiation. New data demonstrates that the histological subtype – more so than the anatomical location – is an important independent prognostic factor. This fuels the discussion about maintaining ampullary cancer as a separate entity.
Autoimmune pancreatocholangitis (AIPC) is an emerging, not completely characterized disease. Aim of this study was the comprehensive evaluation of a series of AIPC patients, who were diagnosed and treated in a European institution between January 2003 and July 2006.
Thirty-three patients with histologically confirmed AIPC were analyzed and compared to 20 patients with non-autoimmune chronic pancreatitis (CP) and 14 patients with primary sclerosing cholangitis (PSC). Clinical features and conventional histopathology were taken into account. Immunohistochemistry and real-time quantitative PCR were used for the characterization of the inflammatory infiltrate and the stromal reaction. AIPC was localized in the pancreatic head in 94% of the patients. Intra- and/or extrapancreatic biliary tract involvement was present in 64% of the cases. The number of infiltrating T-lymphocytes, macrophages and total plasma cells was significantly higher in AIPC than in CP (3-, 4- and 8-fold increase, respectively). The absolute number of IgG4-positive plasma cells was higher in AIPC than in CP and PSC (7-fold and 35-fold increase, respectively), but significance was only reached in comparison with PSC. CXCR5- and CXCL13-positive cells were almost exclusively detected in AIPC.
AIPC is mainly a disease of the pancreatic head with possible extension into the periphery of the gland and/or into the biliary tract/gallbladder. The morphology of AIPC, as well as the immune- and stromal reaction is characteristic and comparable between cases with and without biliary tract involvement. Immunological markers (IgG4, CXCR5, CXCL13) can be of diagnostic relevance in specific settings.
Although considered the reference standard for generating valid scientific evidence of a treatment's benefits and harms, the number of Randomised Controlled Trials (RCT) comparing surgical techniques remains low. Much effort has been made in order to overcome methodological issues and improve quality of RCTs in surgery. To the present there has been, however, only little emphasis on development and maintenance of institutions for implementation of adequately designed and conducted surgical RCTs.
Description of the developments in surgical RCT infrastructure in Germany between 2001 and 2006. Cross sectional evaluation of completed and ongoing surgical RCTs within the German Surgical Society and the Clinical Study Centre, Department of Surgery, University of Heidelberg.
Foundation of a national Clinical Trial Centre (CTC) for the organisation of multi-centre RCTs in the surgical setting (Study Center of the German Surgical Society, SDGC). Establishment of a network of CTCs with affiliated Clinical Sites (CSs) to enhance patient recruitment and shorten the duration of RCTs. Since its foundation four surgical RCTs with a total sample size of 1650 patients (1006 of these randomised) have been supervised by the SDGC with 35 CSs involved in patient recruitment. Five further CTCs were set up in 2006. Together with their affiliated CSs a network has been organised providing improved conditions for the conduction of surgical RCTs.
Improvement of infrastructure substantially facilitates integration of RCTs into routine surgical practice. A network of collaborating CTCs and CSs can provide an adequate infrastructure for the conduction of multi-centre RCTs.