Core content for venous and Lymphatic Medicine: 2022 revision.

The core content for a medical specialty outlines the scope of the discipline as well as the categories of knowledge considered essential to practice in the field. It provides a template for the development of curricula for medical school, graduate, and postgraduate education, as well as for creating certification standards. Venous and Lymphatic Medicine (VLM) is a specialty that has benefitted from contributions from specialists from several medical disciplines. Optimally, the societies, boards, and residency review committees representing these disciplines would uniformly recognize the scope of VLM to develop education and assessment standards to allow training and identification of qualified practitioners. In order to inform the standard setting bodies and other stakeholders of the current scope of VLM, a task force of VLM experts from cardiology, dermatology, emergency medicine, general surgery, interventional radiology, vascular medicine, and vascular surgery was formed to revise a 2014 consensus document defining the core content of the specialty of VLM.

A novel pancreatic tumour and stellate cell 3D co-culture spheroid model.

BACKGROUND: Pancreatic ductal adenocarcinoma is a devastating disease with poor outcome, generally characterized by an excessive stroma component. The purpose of this study was to develop a simple and reproducible in vitro 3D-assay employing the main constituents of pancreatic ductal adenocarcinoma, namely pancreatic stellate and cancer cells. METHOD: A spheroid assay, directly co-culturing human pancreatic stellate cells with human pancreatic tumour cells in 3D was established and characterized by electron microscopy, immunohistochemistry and real-time RT-PCR. In order to facilitate the cell type-specific crosstalk analysis by real-time RT-PCR, we developed a novel in vitro 3D co-culture model, where the participating cell types were from different species, human and mouse, respectively. Using species-specific PCR primers, we were able to investigate the crosstalk between stromal and cancer cells without previous cell separation and sorting. RESULTS: We found clear evidence for mutual influence, such as increased proliferation and a shift towards a more mesenchymal phenotype in cancer cells and an activation of pancreatic stellate cells towards the myofibroblast phenotype. Using a heterospecies approach, which we coined virtual sorting, confirmed the findings we made initially in the human-human spheroids. CONCLUSIONS: We developed and characterized different easy to set up 3D models to investigate the crosstalk between cancer and stroma cells for pancreatic cancer.

Conservative Treatment of Chronic Pancreatitis: A Practical Approach.

BACKGROUND: Chronic pancreatitis is a long-standing, inflammatory condition of the pancreas that leads to the progressive damage and loss of function of pancreatic parenchyma and to the development of possible locoregional and systemic medical complications. MATERIALS AND METHODS: In this review, we tried to summarize the current evidence on non-surgical treatment trying to suggest a practical approach to the management of chronic pancreatitis. RESULTS: Besides the unclear pathophysiological mechanism and a poorly unknown epidemiology, chronic pancreatitis is a complex syndrome that displays different possible challenges for physicians. Despite being traditionally considered as a benign disease, chronic pancreatitis encompasses 10-year mortality rates which are superior to the ones reported for some of the most common cancers. CONCLUSIONS: Chronic pancreatitis encompasses the management of multiple and complex medical co-morbidities that needs to be understood and addressed in a multidisciplinary specialist context.

The ageing pancreas: a systematic review of the evidence and analysis of the consequences.

Senior people constitute the fastest growing segment of the population. The elderly are at risk for malnutrition, thought to be caused by reduced food intake or involution of the physiological capacity of the GI tract. Age-related changes are well known in other secretory organs such as liver, kidney and intestine. The pancreas, representing a metabolically active organ with uptake and breakdown of essential nutritional components, changes its morphology and function with age. During childhood, the volume of the pancreas increases, reaching a plateau between 20 and 60 years, and declines thereafter. This decline involves the pancreatic parenchyma and is associated with decreased perfusion, fibrosis and atrophy. As a consequence of these changes, pancreatic exocrine function is impaired in healthy older individuals without any gastrointestinal disease. Five per cent of people older than 70 years and ten per cent older than 80 years have pancreatic exocrine insufficiency (PEI) with a faecal elastase-1 below 200 µg g-1 stool, and 5% have severe PEI with faecal elastase-1 below 100 µg g-1 stool. This may lead to maldigestion and malnutrition. Patients may have few symptoms, for example steatorrhoea, diarrhoea, abdominal pain and weight loss. Malnutrition consists of deficits of fat-soluble vitamins and is affecting both patients with PEI and the elderly. Secondary consequences may include decreased bone mineral density and results from impaired absorption of fat-soluble vitamin D due to impaired pancreatic exocrine function. The unanswered question is whether this age-related decrease in pancreatic function warrants therapy. Therapeutic intervention, which may consist of supplementation of pancreatic enzymes and/or vitamins in aged individuals with proven exocrine pancreas insufficiency, could contribute to healthy ageing.

Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer.

OBJECTIVE: Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery. DESIGN: Gemcitabine metabolites were analysed in LSL-KrasG12D/+ ; LSL-Trp53R172H/+ ; Pdx-1-Cre (KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry. Functional and preclinical experiments, as well as expression analysis of stromal markers and gemcitabine metabolism pathways were performed in murine and human specimen to investigate the preclinical implications and the mechanism of gemcitabine accumulation. RESULTS: Gemcitabine accumulation was significantly enhanced in fibroblast-rich tumours compared with liver metastases and normal liver. In vitro, significantly increased concentrations of activated 2',2'-difluorodeoxycytidine-5'-triphosphate (dFdCTP) and greatly reduced amounts of the inactive gemcitabine metabolite 2',2'-difluorodeoxyuridine were detected in PSCs and CAFs. Mechanistically, key metabolic enzymes involved in gemcitabine inactivation such as hydrolytic cytosolic 5'-nucleotidases (Nt5c1A, Nt5c3) were expressed at low levels in CAFs in vitro and in vivo, and recombinant expression of Nt5c1A resulted in decreased intracellular dFdCTP concentrations in vitro. Moreover, gemcitabine treatment in KPC mice reduced the number of liver metastases by >50%. CONCLUSIONS: Our findings suggest that fibroblast drug scavenging may contribute to the clinical failure of gemcitabine in desmoplastic PDAC. Metabolic targeting of CAFs may thus be a promising strategy to enhance the antiproliferative effects of gemcitabine.

Endoscopic classification of the papilla of Vater. Results of an inter- and intraobserver agreement study.

BACKGROUND: Many endoscopists acknowledge that the appearance of the papilla of Vater seems to affect biliary cannulation. To assess the association between the macroscopic appearance of the papilla and biliary cannulation and other related clinical issues, a system is needed to define the appearance of the papilla. OBJECTIVE: The purpose of this study was to validate an endoscopic classification of the papilla of Vater by assessing the interobserver and intraobserver agreements among endoscopist with varying experience. METHODS: An endoscopic classification, based on pictures captured from 140 different papillae, containing four types of papillae was proposed. The four types are (a) Type 1: regular papilla, no distinctive features, 'classic appearance'; (b) Type 2: small papilla, often flat, with a diameter ≤ 3 mm (approximately 9 Fr); (c) Type 3: protruding or pendulous papilla, a papilla that is standing out, protruding or bulging into the duodenal lumen or sometimes hanging down, pendulous with the orifice oriented caudally; and (d) Type 4: creased or ridged papilla, where the ductal mucosa seems to extend distally, rather out of the papillary orifice, either on a ridge or in a crease. To assess the level of interobserver agreement, a web-based survey was sent out to 18 endoscopists, containing 50 sets of still images of the papilla, distributed between the four different types. Three months later a follow-up survey, with images from the first survey was sent to the same endoscopists. RESULTS: Interobserver agreement was substantial (κ = 0.62, 95% confidence interval (CI) 0.58-0.65) and were similar for both experts and non-experts. The intraobserver agreement assessed with the second survey was also substantial (κ = 0.66, 95% CI 0.59-0.72). CONCLUSION: The proposed endoscopic classification of the papilla of Vater seems to be easy to use, irrespective of the level of experience of the endoscopist. It carries a substantial inter- and intraobserver agreement and now the clinical relevance of the four different papilla types awaits to be determined.

Disgust mediates the relation between attentional shifting and contamination aversion.

BACKGROUND AND OBJECTIVES: Aversion of contaminants is important for several psychiatric disorders, particularly contamination-based obsessive-compulsive disorder (OCD). Recent theoretical models have proposed that the ability to control one's attention, especially when processing affectively laden information, is important in the etiology of pathological anxiety. The present study tested the relations between attentional control, affective arousal, and behavioral approach toward contaminants (contamination aversion). METHODS: Thirty-three non-selected (undergraduate university students) participants completed a measure of trait attentional control and three behavioral approach tasks, which measured emotional reactivity and approach toward contaminants. RESULTS: Preliminary analyses showed that poorer attentional control and greater affective arousal predicted less behavioral approach toward contaminants. Modeling of direct and indirect relations showed that poor attentional shifting ability and greater subjective disgust were related to less behavioral approach. Moreover, disgust fully mediated the relation between attentional shifting and behavioral approach. LIMITATIONS: The present study used a convenience sample, which is not representative of the general population or individuals with OCD; therefore, research using clinical samples is necessary before making clinical interpretations. Moreover, the present study utilized subjective measures of attentional control and affective arousal. The use of objective measures of attention and affective arousal would provide a more valid test of the role of attentional control in contamination aversion. CONCLUSIONS: These findings suggest that attentional shifting abilities may serve as a vulnerability to affective arousal/regulation and behavioral avoidance of contaminants, but the latter relation only operated indirectly via disgust. These findings have clear implications for the etiology of contamination-related OCD.

Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a randomized controlled phase II trial.

BACKGROUND: Paclitaxel embedded in cationic liposomes (EndoTAG™-1; ET) is an innovative agent targeting tumor endothelial cells. This randomized controlled phase II trial evaluated the safety and efficacy of ET in combination with gemcitabine (GEM) in advanced pancreatic cancer (PDAC). PATIENTS AND METHODS: Chemotherapy-naive patients with locally advanced or metastatic disease were randomly assigned to receive weekly GEM 1000 mg/m(2) or GEM plus twice-weekly ET 11, 22 or 44 mg/m(2) for 7 weeks. After a safety run-in of 100 patients, a second cohort continued treatment. End points included overall survival (OS), progression-free survival (PFS), tumor response and safety. RESULTS: Two hundred and twelve patients were randomly allocated to the study and 200 were treated (80% metastatic, 20% locally advanced). Adverse events were manageable and reversible. Transient thrombocytopenia and infusion reactions with chills and pyrexia mostly grade 1 or 2 occurred in the ET groups. Disease control rate after the first treatment cycle was 43% with GEM and 60%, 65% and 52% in the GEM + ET cohorts. Median PFS reached 2.7 compared with 4.1, 4.6 and 4.4 months, respectively. Median OS was 6.8 compared with 8.1, 8.7 and 9.3 months, respectively. CONCLUSIONS: Treatment of advanced PDAC with GEM + ET was generally well tolerated. GEM + ET showed beneficial survival and efficacy. A randomized phase III trial should confirm this positive trend.

[Autoimmune pancreatitis]. / Autoimmune Pankreatitis.

Autoimmune pancreatitis has been established as a special entity of pancreatitis. It is an enigmatic disease since it is adding an autoimmune etiology to the existing causes of pancreatitis. Morphological hallmarks of the disease are narrowing of the pancreatic duct system and the bile duct by periductal lymphoplasmocytic inflammation. This results in many cases in obstructive jaundice due to a mass-forming lesion in the pancreatic head mimicking pancreatic ductal adenocarcinoma. Therefore, patients will frequently undergo surgery. Histopathologically, the disease can be diagnosed by IgG4-positive plasma cells. Serologically, patients may present with elevated serum IgG and IgG4 levels. Other autoantibodies are also described. Association with other autoimmune manifestations in a wide range of organs is frequent. Autoimmune pancreatitis will respond to steroid treatment, which is of specific importance because pancreatic cancer is one of its clinical differential diagnoses. It is important to positively diagnose autoimmune pancreatitis, especially if the bile ducts are affected, since cholangitis may be or become a prominent problem before or after surgery.

[Proteome analysis--basis for individualized pancreatic carcinoma therapy?]. / Proteomanalyse. Basis für individualisierte Pankreaskarzinomtherapie?

Ductal pancreatic adenocarcinoma is a dismal disease, having the worst prognosis of all solid tumors. While genomics and transcriptomics have provided a wealth of data, no contribution has been made to clinical medicine in terms of diagnostic or prognostic markers. Hope lies in yet another novel technology, proteomics. Conceptually, proteomics bears the advantage of incorporating both posttranslational modifications as well as host factors. This is thought to be important in factors influencing survival such as chemoresistance. This tutorial review discusses the state of the art in pancreatic cancer proteomics in light of technical developments. At this moment, proteomics is still at the beginning in clinical application. First results, however, suggest some hope for the development of a new understanding of the molecular biology in pancreatic cancer yielding into very specific markers of disease or allowing a rational and individualized therapy.

[Indications for pancreatic biopsy. Uncommon, but increasingly more important]. / Indikationen zur Pankreasbiopsie. Selten, aber zunehmend bedeutsamer.

Pancreatic biopsy is an invasive diagnostic method that is only performed when all other diagnostic measures for establishing the diagnosis of a tumorous lesion of the pancreas have failed. Because of the advances in modern imaging techniques, fine needle biopsy of the pancreas guided by ultrasonography, computer tomography or endosonography has become a reliable method that allows the diagnosis of ductal adenocarcinoma or any of the other, rarer pancreatic tumors with high sensitivity and specificity. Complications are rare, particularly with the endosonographically guided biopsy. A new biopsy indication is the demonstration of certain markers or gene mutations that are needed for the initiation of special treatments, e.g. EGFR-Cetuximab.

[The diagnostic validity of non-invasive pancreatic function tests--a meta-analysis]. / Die diagnostische Validität nichtinvasiver Pankreasfunktionstests -- Eine Metaanalyse.

BACKGROUND: The paper discusses the non-invasive (tubeless) pancreatic function tests used to diagnose exocrine pancreatic insufficiency (EI). Studies evaluating the diagnostic validity of these tests are integrated into a meta-analysis, provided that they comply with the following criteria: The sensitivity (Ss) of a test has to be calculated by comparing it with an invasive function test which is accepted as the gold standard of pancreatic function diagnostics. Furthermore, the test must differentiate between slight (sl), moderate (md) and severe (sv) EI. For assessment of the specificity (Sp), the control group should not contain healthy persons but rather patients with other gastrointestinal diseases and a normal pancreatic function. In the statistical evaluation, each study was weighted according to the number of persons included. RESULTS: Tests (n = sum of persons included in all analysed studies): Fecal chymotrypsin: Ss (n = 169) 54 % (sl EI), 53 % (md EI), 89 % (sv EI), Sp (n = 202) 74 %. NBT-PABA test: Ss (n = 394) 49 % (sl EI), 64 % (md EI), 72 % (sv EI), Sp (n = 218) 83 %. Pancreolauryl test: Ss (n = 320) 63 % (sl EI), 76 % (md EI), 94 % (sv EI), Sp (n = 171) 85 %. Fecal elastase-1: Ss (n = 307) 54 % (sl EI), 75 % (md EI), 95 % (sv EI), Sp (n = 347) 79 %. Additional tests discussed but not included in the meta-analysis were fecal fat, (13)C breath tests, amino acid consumption test, serum tests. CONCLUSION: None of the non-invasive pancreatic function tests is sensitive enough to diagnose reliably a slight to moderate exocrine pancreatic insufficiency.

Sakai et al. is not an adequate demonstration of TFT effectiveness.

Sakai et al. (2001) report an uncontrolled case series of TFT treatments applied to a wide range of psychological complaints in a large health maintenance facility. They analyze verbal report measures of symptom severity and conclude that the specific treatment is effective for a wide range of psychological problems. A review of the theory and research on TFT efficacy indicates that the theoretical basis for the specific treatment is unfounded and that adequately controlled efficacy research has yet to be conducted. The authors' conclusions about effectiveness and applicability are not supported by either theory, prior research, or the findings of their clinical application.

Low frequency of p53 and ras mutations in bile of patients with hepato-biliary disease: a prospective study in more than 100 patients.

The diagnosis of biliary disease, namely malignant disorders, is frequently hampered by the inconclusive cytology. We investigated prospectively the frequency of molecular changes in p53 and ras compared with cytology in patients with primary or secondary hepato-biliary disease. We investigated 118 consecutive patients, aged 24-89 with the following clinical diagnoses: choledocho/cholecystolithiasis (28), cholangiocellular carcinoma (21), gall bladder tumor (8), liver metastasis (3), autoimmune disease (8), chronic pancreatitis (16), pancreatic carcinoma (11), papillary disease (4), hepatic cirrhosis (6), cholangitis (2), anomalies (2), and normal (9). Bile was aspirated during routine endoscopic retrograde cholangio pancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC). DNA was prepared freshly from a native aliquot. p53 mutations were detected by polymerase chain reaction (PCR) for exons 5 through 8 followed by TGGE. PCR for ras mutations was performed as RFLP-PCR with sequencing. In four cases, mutations in p53 could be found in exons 6 and 7. Twenty-two samples showed ras mutations; ras mutations were found in choledocholithiasis (4/28), bile duct (5/21), gall bladder (3/8) and pancreatic (1/11) carcinoma, liver metastasis (3/3), ulcerative colitis (2/3), PSC (1/2), and chronic pancreatitis (1/16). Cytology was clearly positive in seven cases, suspicious in three other, inconclusive in six, and negative in the rest. The molecular analysis resulted in a sensitivity of 33% and specificity of 87%, respectively, for the diagnosis of a malignant condition. PCR for p53 and ras mutations may aid the diagnosis of primary and secondary (metastatic) hepatobiliary disease if a malignant condition of the bile ducts and the liver is suspected and cytology is inconclusive or negative. However, the incidence of p53 and ras mutations in bile seems less frequent than in other malignant conditions of the gastrointestinal tract and the pancreas and lower than in tissue, leaving a poor sensitivity and specificity. Nevertheless, the presence of a p53 and/or ras mutation per se supports a clinical suspicion of malignancy, even when the conventional cytology is negative or inconclusive.

[Palliative therapy of pancreatic adenocarcinoma]. / Palliative Therapie des Pankreasadenokarzinoms.

The palliative therapy of pancreatic carcinoma consists of best supportive care (BSC) including nutritional and pain therapy, and antineoplastic remedies. This is complemented by interventional endoscopy aiming to treat obstructive jaundice and/or gastric or duodenal obstruction by implantation of endoprostheses. Pain therapy is standardized for the most part according to the WHO guidelines; nutrition of the cancer patient, however, is sometimes disregarded. For palliative chemotherapy, 5-fluorouracil and gemcitabine can be recommended. Combinations thereof with other cytostatic drugs or radiation are subject to ongoing studies. A variety of novel therapeutic concepts, e.g. immunomodulation or suicide gene therapy, have demonstrated good effects in animal studies. Unfortunately, very few of these have entered clinical studies (phase I and phase II). This will be the focus of future research in this field.

Carotid thromboendarterectomy for recent total occlusion of the internal carotid artery.

BACKGROUND: The efficacy of emergency carotid thromboendarterectomy (CTEA) for acute internal carotid artery (ICA) thrombosis has been questioned. We evaluated the use of CTEA in patients with recent ICA occlusion. METHODS: From August 1989 to December 1999 patients who underwent urgent CTEA for recent ICA thrombosis were retrospectively evaluated. Patient data analyzed included age, sex, comorbid risk factors, diagnostic evaluation, operative procedure, and long-term follow-up with clinical assessment and carotid duplex scan. Neurologic status was evaluated with the Modified Rankin Scale (MRS) before the operation, immediately after the operation, and at 3- to 6-months' follow-up. RESULTS: Twenty-nine patients underwent emergency ipsilateral CTEA for acute ICA thrombosis over the last 10 years. The average age of the patients was 69.9 +/- 1.7 years, and 66% were men. Patient risk factors included diabetes (7 [24%]), hypertension (21 [72%]), coronary artery disease (8 [29%]), and history of tobacco abuse (20 [69%]). Presenting symptoms included cerebrovascular accident (7 [24%]), transient ischemic attack (nonamaurosis) (10 [34%]), crescendo transient ischemic attack (7 [24%]), stroke in evolution (2 [7%]), and amaurosis fugax (3 [10%]). Diagnostic evaluation included computed tomographic scan (29 [100%]), magnetic resonance imaging/magnetic resonance angiography (4 [14%]), duplex scan evaluation of the carotid arteries (23 [79%]), and cerebral angiography (18 [64%]). Antegrade flow in the ICA was successfully established in 24 (83%) of 29 patients and confirmed with intraoperative angiography or duplex sonography. Postoperative morbidity included 2 hematomas (7%), 4 transient cranial nerve deficits (14%), and 1 conversion to hemorrhagic stroke (3.6%), which resulted in the only death (3.6%). MRS scores averaged 3.4 +/- 0.2 preoperatively. Follow-up averaging 74.1 +/- 21 months (range, 3-140 months) was obtained in 27 (93%) patients. Improvement or deterioration was defined as a change in MRS +/- 1. Immediately postoperatively, 14 (48%) patients were improved, 2 (7%) deteriorated, and 13 (45%) had no change. At 3 to 6 months, 20 (74%) of 27 patients were improved, seven (26%) had no change, and none deteriorated. Of patients with successful CTEA, 23 (96%) of 24 had a patent ICA on follow-up duplex scan evaluation, and there was no evidence of recurrent ipsilateral neurologic events at an average of 49 months. CONCLUSION: These data support an aggressive early surgical intervention for acute ICA thrombosis in carefully selected patients. In the previous decade we reported a 46% success rate for establishing antegrade flow in the ICA long term. Data from this decade show a 79% (P =.0114) success rate for establishing antegrade flow long term in all patients undergoing emergency CTEA. New and improved imaging modalities have allowed better patient selection, resulting in improved outcomes.