A prospective survey study on the education and awareness about walking exercise amongst inpatients with symptomatic peripheral arterial disease in Germany.

Background: To determine the adherence to supervised exercise training and underlying reasons for non-adherence amongst patients with inpatient treatment of symptomatic lower extremity peripheral arterial disease (PAD). Patients and methods: This was a prospective questionnaire-based survey study of all consecutively treated inpatients with treatment for either intermittent claudication or chronic limb-threatening ischaemia (CLTI) surveyed at sixteen participating centres in Germany. Results: A total of 235 patients (median age 70 years) were included, thereof 29.4% females and 34.6% with CLTI. The median time from first PAD diagnosis was 4 years (IQR: 1-8). Only 11.4% have previously participated in any walking exercise programme before the index treatment, thereby 10.0% in the IC subgroup and 12.0% with CLTI. Amongst all patients, 35.6% responded they were appropriately informed about the necessity and benefits of walking exercise programmes by their hospital physicians (25.8% by general practitioners), and 65.3% agreed that adherence to supervised exercise may improve their pain-free walking distance. A total of 24.5% responded they had access to necessary information concerning local walking exercise programmes. Amongst 127 free text comments on the reasons for non-adherence to supervised exercise training, 64% of the comments contained lack of information or consent on such measures. Conclusions: Less than 12% of the patients enrolled in the current study have ever participated in a walking exercise programme during their life course. Although all practice guidelines contain corresponding class I recommendations, especially for patients suffering from IC, most patients responded that they were not appropriately informed about the necessity of exercise training along with the fact that 65% agreed that exercise may increase the pain-free walking distance. Taken all together, these results emphasise that we miss an important opportunity in the patient-physician communication. Efforts should be made to improve acceptance and application of structured walking-exercise for patients with PAD.

[Diagnosis and Management of Perioperative Myocardial Ischemia after Elective Aortic Aneurysm Surgery]. / Diagnostik und Management der perioperativen Myokardischämie im Rahmen elektiver Eingriffe bei Aortenaneurysmen.

INTRODUCTION: Perioperative myocardial ischemia (PMI) is a serious postoperative complication. Aortic operations represent an especially high-risk surgery concerning cardiac complications. This aim of this study was to analyse the clinical features of PMI after elective aortic aneurysm surgery. PATIENTS AND METHODS: This study is a retrospective analysis of 863 patients who underwent elective aortic aneurysm surgery between 2005 and 2012 in the Department of Vascular and Endovascular Surgery of Heidelberg University Hospital with regard to PMI. The PMI diagnosis was based on a positive serum troponin diagnostic test. We evaluated the clinical course, time point of the diagnosis and features of diagnostics to characterise PMI. Moreover, we analysed the treatment options and management of the patients' discharge. RESULTS: Thirty-one patients (3.6% of 863) with PMI after elective aortic aneurysm surgery were identified. Of these, 21 patients (67.7%) underwent open surgery and 10 patients (32.3%) received endovascular treatment. PMI was diagnosed in 24 patients (77%) during the first 3 days. More than half of these patients (16/31) were clinically asymptomatic. Electrocardiogram did not show pathological findings in 24 cases (77.4%). The first troponin measurement was not elevated in eight patients (25.8%). Drug therapy alone was used in 17 cases (54.8%) of PMI, coronary catheterisation was performed in 12 patients (38.7%) and two patients (6.5%) received aortocoronary bypass. Fourteen patients (45.1%) were discharged home and another 14 patients (44.1%) were transferred to another hospital or to a rehabilitation institution. Two patients died because of multi-organ failure. CONCLUSION: PMI is not a rare complication after elective aortic surgery. The diagnosis of PMI can be challenging because of occult symptoms especially in a perioperative setting. Due to the potentially serious consequences, cardiac enzyme diagnostics should be initiated immediately if there is suspicion of PMI or routinely in defined at-risk patients after aortic surgery.

Outcome Analysis and Risk Factors for Perioperative Myocardial Ischemia After Elective Aortic Surgery.

BACKGROUND: Perioperative myocardial ischemia (PMI) after non-cardiac surgery remains a serious postoperative complication. This study analyzed the risk factors and outcomes of patients who suffered from PMI after elective aortic surgery. PATIENTS AND METHODS: Data from 863 patients who underwent elective aortic surgery for aneurysms or Leriche syndrome were retrospectively analysed with regard to PMI. The diagnosis of PMI was based on a positive serum troponin diagnostic test. According to the clinical signs and symptoms, the patients with PMI were divided into two groups: symptomatic and asymptomatic patients. Comorbidities, preoperative medication, intraoperative parameters, postoperative complications, mortality, length of intensive care stay and hospitalisation, as well as the long-term follow-up, were compared in a matched-pair analysis (1:3) with patients without PMI. Logistic regression analyses were performed to identify independent risk factors for PMI. RESULTS: Thirty-two patients with PMI were identified. Cardiac comorbidities (previous myocardial ischemia, P = 0.0099; left ventricular systolic dysfunction, P = 0.0429), ASA score ≥III (P = 0.0114) and preoperative elevated creatinine (P = 0.0194) were more common in patients who suffered PMI. The regression analysis confirmed that peripheral artery disease and prolonged operative duration >180 min are significant predictors of PMI. Surgical complications (wound healing deficit, P = 0.0027; rate of secondary interventions during primary admission, P = 0.0057) and medical complications (pneumonia, P = 0.0002; renal dysfunction, P = 0.0041) were more common in patients with PMI compared to the control group. Patients who suffered PMI remained in intensive care for a significantly longer period (P = 0.0001) and were also hospitalized for longer (P = 0.0001) than the control group. The long-term survival of patients who suffered PMI after aortic surgery was significantly worse than the control group (P < 0.0001, median 53 vs. 84 months), independent of clinical ischemia-associated symptoms. CONCLUSIONS: PMI after aortic surgery not only affects long-term survival, but also correlates with worsening of surgical outcome. Thus, meticulous preoperative risk stratification is required for high-risk patients, together with routine postoperative monitoring of troponin levels after aortic surgery.

Extended intensive care correlates with worsening of surgical outcome after elective abdominal aortic reconstruction.

BACKGROUND: The aim of this study was to evaluate the impact of extended postoperative intensive care on short- and long-term patient outcome after elective abdominal aortic surgery and to assess the risk factors for patient survival after extended intensive care unit (ICU) treatment. METHODS: The data of 231 patients that underwent open or endovascular abdominal aortic surgery were retrospectively analysed with regard to extended postoperative intensive care, defined as ICU treatment for more than 24 consecutive hours. Pre- and intraoperative factors were evaluated. The endpoints of the study were postoperative complications, mortality, and long-term follow-up. Univariate and multivariate Cox proportional regression analyses were performed to identify risk factors of worse overall survival. RESULTS: Extended postoperative intensive care was needed in 84 patients (63 after open and 21 after endovascular surgery). The period of ICU treatment was similar in both groups. Only the wound complications (31.8% vs. 9.5%, P=0.0498; OR 4.42 [0.94-20.84]) and the rate of acute kidney injury (82.5% vs. 57.1%, P=0.0352; OR 3.55 [1.20-0.46]) were more frequent after open surgery, whereas brief reactive psychosis (38.1% vs. 14.3%, P=0.0281; OR 0.27 [0.09-0.84]) was more frequent after endovascular surgery. ICU stay of ≥8 days correlated with significantly lower survival rates compared to a shorter ICU stay (P=0.0034), independent of open or endovascular techniques. Other multivariate risk factors for worse survival were the absence of preoperative aspirin medication, a Body Mass Index (BMI) of <25, chronic renal insufficiency, and coronary artery disease. Endovascular therapy was a positive predictive factor of short ICU stay of ≤3 days. CONCLUSIONS: The outcome after extended intensive care following elective aortic surgery is strongly dependent on the length of ICU stay.

Outcome analysis and risk factors for postoperative colonic ischaemia after aortic surgery.

PURPOSE: Colonic ischaemia (CI) represents a serious complication after aortic surgery. This study aimed to analyse risk factors and outcome of patients suffering from postoperative CI. METHODS: Data of 1404 patients who underwent aortic surgery were retrospectively analysed regarding CI occurrence. Co-morbidities, procedural parameters, colon blood supply, procedure-related morbidity and mortality as well as survival during follow-up (FU) were compared with patients without CI using matched-pair analysis (1:3). RESULTS: Thirty-five patients (2.4%) with CI were identified. Cardiovascular, pulmonary and renal comorbidity were more common in CI patients. Operation time was longer (283 ± 22 vs. 188 ± 7 min, p < 0.0001) and blood loss was higher (2174 ± 396 vs. 1319 ± 108 ml, p = 0.0049) in the CI group. Patients with ruptured abdominal aortic aneurysm (AAA) showed a higher rate of CI compared to patients with intact AAA (5.4 vs. 1.9%, p = 0.0177). CI was predominantly diagnosed by endoscopy (26/35), generally within the first 4 postoperative days (20/35). Twenty-eight patients underwent surgery, all finalised with stoma creation. Postoperative bilateral occlusion and/or relevant stenosis of hypogastric arteries were more frequent in CI patients (57.8 vs. 20.8%, p = 0.0273). In-hospital mortality was increased in the CI group (26.7 vs. 2.9%, p < 0.0001). Survival was significantly reduced in CI patients (median: 28.2 months vs. 104.1 months, p < 0.0001). CONCLUSION: CI after aortic surgery is associated with considerable perioperative sequelae and reduced survival. Especially in patients at risk, such as those with rAAA, complicated intraoperative course, severe cardiovascular morbidity and/or perioperative deterioration of the hypogastric perfusion, vigilant postoperative multimodal monitoring is required in order to initiate diagnosis and treatment.

[Colonic ischemia after open and endovascular aortic surgery : Epidemiology, Risk Factors, Diagnosis And Therapy]. / Kolonischämie nach offener und endovaskulärer Aortenchirurgie : Epidemiologie, Risikofaktoren, Diagnostik und Therapie.

Despite the successful establishment of endovascular techniques, colonic ischemia continues to be a serious complication of aortic surgery.The risk factors for colonic ischemia include aortic aneurysm rupture, prolonged aortic clamping, perioperative hypotension, the need for catecholamine therapy, occlusion of the hypogastric arteries and renal insufficiency.The clinical presentation of postoperative colonic ischemia is often unspecific. Classic symptoms include abdominal pain, diarrhea, peranal bleeding and rise of inflammatory parameters. A specific laboratory parameter for colonic ischemia does not exist. The diagnostic gold standard is endoscopy. Imaging methods such as sonography or computer tomography play only a supportive role. Transmural ischemia resulting in bowel wall necrosis is an indication for emergency surgery, predominantly colonic resection with creation of artificial anus.

Short-term Results of the RAPID Randomized Trial of the Legflow Paclitaxel-Eluting Balloon With Supera Stenting vs Supera Stenting Alone for the Treatment of Intermediate and Long Superficial Femoral Artery Lesions.

PURPOSE: To report a randomized trial comparing the Legflow paclitaxel-eluting balloon (PEB) + Supera stenting to Supera stenting alone in patients with intermediate to long superficial femoral artery (SFA) lesions. METHODS: The multicenter RAPID trial ( controlled-trials.com ; identifier ISRCTN47846578) randomized (1:1) 160 patients (mean age 67 years; 102 men) with Rutherford category 2-6 ischemia to treatment with Legflow PEB + Supera stent or Supera stent alone in intermediate to long SFA lesions (mean lesion length 15.8±7.4 vs 15.8±7.6 cm, respectively). The efficacy outcome was primary patency, defined as freedom from restenosis on duplex ultrasound or angiography. RESULTS: Baseline characteristics including the percentage of occlusions were similar between groups. In the intention-to-treat analysis, the estimated primary patency at 1 year was 68.3% (95% CI 56.7% to 79.9%) in the PEB + Supera group vs 62.0% (95% CI 49.1% to 74.9%) in the Supera group (p=0.900). Per-protocol analysis showed a 12-month primary patency estimate of 74.7% (95% CI 63.1% to 86.3%) in the PEB + Supera group vs 62.0% (95% CI 49.1% to 74.9%) in the control group (p=0.273). Secondary patency estimates at 12 months (per-protocol analysis) were 89.0% (95% CI 80.6% to 97.4%) vs 98.0% (95% CI 94.1% to 100%; p=0.484); the estimates for freedom from clinically driven target lesion revascularization (CD-TLR) were 83.0% (95% CI 72.8% to 93.2%) and 77.8% (95% CI 66.6% to 89.0%; p=0.277), respectively. CONCLUSION: The short-term results from the multicenter RAPID randomized controlled trial indicate that the Legflow PEB is safe and feasible for the treatment of intermediate to long SFA lesions. In this trial, at least 70% of the patients suffered an occlusion. The PEB group had higher rates of primary patency and freedom from CD-TLR, although there were no statistically significant differences vs controls.

Objective parameters aid the prediction of fistulas in pancreatic surgery.

Insufficiency of pancreatic anastomosis with leakage from the pancreatic stump and the development of fistulas account for the majority of surgical complications following pancreatic resection, which are often life threatening. The cause of pancreatic fistulas of the remnant tissue on a molecular level remains unclear. Thus, the aim of the present study was to investigate risk factors associated with postoperative pancreatic fistula (POPF) formation and to define parameters that may predict the resection outcome. Pancreatic resection margins were selected from 31 patients, including 16 individuals without and 15 patients with POPF, to analyze the degree of fibrosis, lipomatous atrophy, inflammatory activity and infiltration. Wound healing factors were assessed by luminex technology using tissue homogenates, while the distribution in situ was assessed using immunohistochemistry. Increased chronic inflammatory infiltration, a higher degree of fibrosis and a reduction in lipomatous atrophy were observed in the samples without anastomotic fistulas. Multiplex analysis of 38 wound healing factors demonstrated significantly higher levels of interleukin (IL)-6, -8 and -12, glucagon-like peptide-1 and matrix metalloproteinase (MMP)-1, -2, -3 and -12 in the group without fistulas, while lower concentrations of IL-10, IL-17 and gastric inhibitory polypeptide were observed. Therefore, the observations of the present study indicated that increased inflammatory infiltration and inflammatory activity, as well as higher concentrations of proinflammatory cytokines and higher MMP levels at the resection margins, predisposed individuals to a lower fistula incidence rate following pancreatic resection.

Clinical impact of perioperative myocardial infarction after pancreatic surgery.

BACKGROUND: The aim of this study was to evaluate the incidence, clinical impact and outcome of perioperative myocardial infarction (PMI) in patients undergoing pancreatic surgery. METHODS: A data of 1,625 patients undergoing pancreatic resection were prospectively collected and analysed with regard to PMI. Demographic aspects, co-morbidities and clinical course were evaluated. Cardiac risk factors (ASA and NYHA), postoperative complications and mortality were compared in a match-pair analysis (1:3) with patients without PMI. RESULTS: Twenty-nine patients with PMI after pancreatic surgery were identified. PMI occurred after all types of pancreatic operations and was observed most frequently (72.2%) within the first postoperative week. In a total of 90%, PMI fulfilled the criteria of non-STEMI. Nearly half of the patients (48%) were clinically asymptomatic. Both ASA III and heart failure were more frequent in patients with PMI. The in-hospital mortality was significantly increased after PMI (p < 0.002), with post-pancreatectomy haemorrhage (PPH) as the most relevant underlying risk factor. CONCLUSION: PMI is a rare but severe complication after pancreatic operations, contributing significantly to in-hospital mortality. Clinical management mainly includes an anti-coagulant approach. This may be related with an increased risk for PPH. Therefore, the use of anti-coagulant drugs in the early postoperative period-especially in asymptomatic patients-should be critically evaluated.

Growth inhibition of pancreatic cancer by experimental treatment with 4-phenylbutyrate is associated with increased expression of Connexin 43.

Histone deacetylase inhibitors are a new and promising drug family with a strong anticancer activity and potent modulation of connexin expression. The restoration of connexins in cancer cells has been suggested as a possible mechanism to control tumor progression. The aim of this study was to investigate the effects of 4-phenylbutyrate (4-PB) on the growth of human pancreatic cell lines in vitro and in vivo with a focus on connexin modulation. The proliferation of tumor cells was determined using an MTT assay, and the effect of 4-PB in vivo was studied in a chimeric mouse model. The expression and localization of connexin 43 (Cx43) were assessed by Western blot, immunofluorescence microscopy, and immunohistochemistry. Antitumoral activity was assessed by immunohistochemistry for Ki-67 and histone H4. Treatment with 4-PB resulted in the significant in vitro and in vivo growth inhibition of pancreatic tumor cells. The reduction of the xenograft tumor volume was associated with the inhibition of histone deacetylation and decrease in cell proliferation. Treatment with 4-PB caused a significant increase in the Cx43 expression in T3M4 cells (up to 2.8-fold). The newly synthesized Cx43 was localized in the cytoplasm but not on the cell membrane. Treatment with 4-PB inhibited the proliferation of human pancreatic tumor cells in vitro and in vivo and increased the expression of Cx43. Therefore, 4-PB might be useful in the therapy of pancreatic cancer.

Experimental in vivo and in vitro treatment with a new histone deacetylase inhibitor belinostat inhibits the growth of pancreatic cancer.

BACKGROUND: Treatment options for pancreatic ductal adenocarcinoma (PDAC) are limited. Histone deacetylase inhibitors are a new and promising drug family with strong anticancer activity. The aim of this study was to examine the efficacy of in vitro and in vivo treatment with the novel pan-HDAC inhibitor belinostat on the growth of human PDAC cells. METHODS: The proliferation of tumour cell lines (T3M4, AsPC-1 and Panc-1) was determined using an MTT assay. Apoptosis was analysed using flow cytometry. Furthermore, p21Cip1/Waf1 and acetylated histone H4 (acH4) expression were confirmed by immunoblot analysis. The in vivo effect of belinostat was studied in a chimeric mouse model. Antitumoural activity was assessed by immunohistochemistry for Ki-67. RESULTS: Treatment with belinostat resulted in significant in vitro and in vivo growth inhibition of PDAC cells. This was associated with a dose-dependent induction of tumour cell apoptosis. The apoptotic effect of gemcitabine was further enhanced by belinostat. Moreover, treatment with belinostat increased expression of the cell cycle regulator p21Cip1/Waf1 in Panc-1, and of acH4 in all cell lines tested. The reductions in xenograft tumour volumes were associated with inhibition of cell proliferation. CONCLUSION: Experimental treatment of human PDAC cells with belinostat is effective in vitro and in vivo and may enhance the efficacy of gemcitabine. A consecutive study of belinostat in pancreatic cancer patients alone, and in combination with gemcitabine, could further clarify these effects in the clinical setting.

Distal pouch reconstruction with transverse jejunoplasty after experimental gastrectomy.

PURPOSE: Various reconstruction methods with or without reservoir formation after total gastrectomy have been established. Transverse intestinoplasty has benefits as a functional peristalsis modification in rectal resections. In this study, we evaluate a distal pouch combined with a transverse jejunoplasty compared to standard Roux-en-Y reconstruction. METHODS: Total gastrectomy was performed on 23 pigs randomly assigned to 3 reconstruction groups-group 1 (n = 7): esophagojejunostomy without a pouch, group 2 (n = 8): esophagojejunostomy with a distal pouch, and group 3 (n = 8): distal pouch with a transverse jejunoplasty. Seven days postoperatively, weight was measured, and X-ray examinations were conducted for 1 h after oral contrast medium application. Blood glucose levels after oral glucose intake and the volume of the pouch loop were evaluated. RESULTS: Upper jejunal passage was delayed and the mean volume of the jejunal loop increased by pouch formation compared to controls (p < 0.05). Body weight was the best for the pouch group with jejunoplasty (-1.9 ± 0.8% vs. pouch alone -3.3 ± 2.4% vs. no pouch -7.5 ± 2.1%, p < 0.05). CONCLUSIONS: The distal jejunal pouch after total gastrectomy offers advantages with respect to bowel passage and postoperative nutrition status compared to standard Roux-en-Y reconstruction. The combination of a distal pouch and transverse jejunoplasty may provide additional functional benefits.

Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the clearance of apoptotic pancreatic carcinoma cells by human macrophages.

Histone deacetylase inhibitors have been found to have potent anticancer activities, partly induced by tumour cell apoptosis. The clearance of apoptotic tumour cells is an important mechanism of antitumour immune surveillance. The aim of this study was to assess the impact of 4-phenylbutyrate (4-PB) and its immunological effects on the macrophage clearance of apoptotic pancreatic ductal adenocarcinoma (PDAC) cells. To this end, a co-culture system of human macrophages from donors and PDAC patients, and PDAC cell lines (T3M4, PANC-1 and AsPC-1) was established to study the effect of 4-PB. Apoptosis and phagocytic activity were analysed using flow cytometry, and phagocytosis was confirmed by confocal microscopy. Further, p21 expression was quantified by immunoblot analysis. 4-PB treatment (0-10 mM) resulted in a dose-dependent induction of tumour cell apoptosis in two of the cell lines (T3M4 and PANC-1), but it also induced human macrophage apoptosis. The apoptotic effect of gemcitabine on PDAC cells was further enhanced by 4-PB. Moreover, 4-PB led to a dose-dependent overexpression of the cell cycle regulator p21 in tumour cells. In co-culture, apoptotic PDAC cells were phagocytosed by donor macrophages and phagocytosis was increased through tumour cell exposure to 4-PB and/or gemcitabine, whereas phagocytosis of PANC-1 cells was reduced using macrophages of PDAC patients treated with 4-PB. The 4-PB treatment induced human macrophage expression of the pro-angiogenic IL-8 and simultaneously inhibited inflammatory cytokine release through modulation of IL-10 and TNFα after phagocytosis of apoptotic PDAC cells. In conclusion, the 4-PB treatment activated tumour cell death in PDAC cells, resulting in tumour cell phagocytosis by macrophages. The latter were characterized by an anti-inflammatory and pro-angiogenic cytokine response demonstrating adverse, tumour-promoting effects of macrophages on tumour cells. Thus, the potential of 4-PB as an anticancer agent against PDAC cannot be reliably assessed without taking into account the complex tumour microenvironment.