[Show abstract][Hide abstract] ABSTRACT: To analyze clinical courses and outcome of postpancreatectomy hemorrhage (PPH) after major pancreatic surgery.
Although PPH is the most life-threatening complication following pancreatic surgery, standardized rules for its management do not exist.
Between 1992 and 2006, 1524 patients operated on for pancreatic diseases were included in a prospective database. A risk stratification of PPH according to the following parameters was performed: severity of PPH classified as mild (drop of hemoglobin concentration <3 g/dL) or severe (>3 g/dL), time of PPH occurrence (early, first to fifth postoperative day; late, after sixth day), coincident pancreatic fistula, intraluminal or extraluminal bleeding manifestation, and presence of "complex" vascular pathologies (erosions, pseudoaneurysms). Success rates of interventional endoscopy and angiography in preventing relaparotomy were analyzed as well as PPH-related overall outcome.
Prevalence of PPH was 5.7% (n = 87) distributed almost equally among patients suffering from malignancies, borderline tumors, and focal pancreatitis (n = 47) and from chronic pancreatitis (n = 40). PPH-related overall mortality of 16% (n = 14) was closely associated with 1) the occurrence of pancreatic fistula (13 of 14); 2) vascular pathologies, ie, erosions and pseudoaneurysms (12 of 14); 3) delayed PPH occurrence (14 of 14); and 4) underlying disease with lethal PPH found only in patients with soft texture of the pancreatic remnant, while no patient with chronic pancreatitis died. Conversely, primary severity of PPH (mild vs. severe) and the kind of index operation (Whipple resection, pylorus-preserving partial pancreaticoduodenectomy, organ-preserving procedures) had no influence on outcome of PPH. Endoscopy was successful in 3 from 15 patients (20%), who had intraluminal PPH within the first or second postoperative day. "True," early extraluminal PPH had uniformly to be treated by relaparotomy. Seventeen patients had "false," early extraluminal PPH due to primarily intraluminal bleeding site from the pancreaticoenteric anastomosis with secondary disruption of the anastomosis. From 43 patients subjected to angiography, 25 underwent interventional coiling with a success rate of 80% (n = 20). Overall, relaparotomy was performed in 60 patients among whom 33 underwent surgery as first-line treatment, while 27 were relaparotomied as rescue treatment after failure of interventional endoscopy or radiology.
Prognosis of PPH depends mainly on the presence of preceding pancreatic fistula. Decision making as to the indication for nonsurgical interventions should consider time of onset, presence of pancreatic fistula, vascular pathologies, and the underlying disease.
Full-text · Article · Aug 2007 · Annals of Surgery
[Show abstract][Hide abstract] ABSTRACT: A pancreatic duct diameter (PDD) ranging from 4 to 5 mm is regarded as "normal." The "large duct" form of chronic pancreatitis (CP) with a PDD >7 mm is considered a classic indication for drainage procedures. In contrast, in patients with so-called "small duct chronic pancreatitis" (SDP) with a PDD <3 mm extended resectional procedures and even, in terms of an "ultima ratio," total pancreatectomy are suggested.
Between 1992 and 2004, a total of 644 patients were operated on for CP. Forty-one prospectively evaluated patients with SDP underwent a new surgical technique aiming at drainage of the entire major PD (longitudinal "V-shaped excision" of the anterior aspect of the pancreas). Preoperative workup for imaging ductal anatomy included ERCP/MRCP, visualizing the PD throughout the entire gland. The interval between symptoms and therapeutic intervention varied from 12 to 120 months. Median follow-up was 83 months (range, 39-117 months). A pain score as well as a multidimensional psychometric quality-of-life questionnaire was used.
Hospital mortality was 0%. The perioperative (30 days) morbidity was 19.6%. Postoperative, radiologic imaging showed an excellent drainage of the entire gland and the PD in all but 1 patient. Global quality-of-life index increased in median by 54% (range, 37.5%-80%). Median pain score decreased by 95%. Twenty-seven patients (73%) had complete pain relief. Sixteen patients (43%) developed diabetes, while the exocrine pancreatic function was well preserved in 29 patients (78%).
"V-shaped excision" of the anterior aspect of the pancreas is a secure and effective approach for SDP, achieving significant improvement in quality of life and pain relief, hereby sparing patients from unnecessary, extended resectional procedures. The deterioration of exocrine and endocrine pancreatic functions is comparable with that observed during the natural course of the disease.
Full-text · Article · Dec 2006 · Annals of Surgery
[Show abstract][Hide abstract] ABSTRACT: To study the prognostic value of adjuvant chemotherapy in patients with pancreatic, ductal adenocarcinoma.
Lymph nodes from 106 patients with resectable pancreatic ductal adenocarcinoma were systematically sampled. A total of 318 lymph nodes classified histopathologically as tumor-free were examined using sensitive immunohistochemical assays. Forty-three (41%) of the 106 patients were staged as pT((1/2)), 63 (59%) as pT((3/4)), 51 (48%) as pN(0), and 55 (52%) as pN(1). The study population included 59 (56%) patients exhibiting G((1/2)), and 47 (44%) patients with G(3) tumors. Patients received no adjuvant chemo- or radiation therapy and were followed up for a median of 12 (range: 3.5 to 139) mo.
Immunostaining with Ber-EP4 revealed nodal microinvolvement in lymph nodes classified as "tumor free" by conventional histopathology in 73 (69%) out of the 106 patients. Twenty-nine (57%) of 51 patients staged histopathologically as pN(0) had nodal microinvolvement. The five-year survival probability for pN0-patients was 54% for those without nodal microinvolvement and 0% for those with nodal microinvolvement. Cox-regression modeling revealed the independent prognostic effect of nodal microinvolvement on recurrence-free (relative risk 2.92, P=0.005) and overall (relative risk 2.49, P=0.009) survival.
The study reveals strong and independent prognostic significance of nodal microinvolvement in patients with pancreatic ductal adenocarcinoma who have received no adjuvant therapy. The addition of immunohistochemical findings to histopathology reports may help to improve risk stratification of patients with pancreatic cancer.
Full-text · Article · Oct 2006 · World Journal of Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis, the process of new vessel formation from a pre-existing vascular network, is essential for bone development and repair. New vessel formation and microvascular functions are crucial during bone repair, not only for sufficient nutrient supply, transport of macromolecules and invading cells, but also because they govern the metabolic microenvironment. Despite its central role, very little is known about the initial processes of vessel formation and microvascular function during bone repair.
To visualize and quantify the process of vessel formation and microvascular function during bone repair, we transplanted neonatal femora with a substantial defect into dorsal skin-fold chambers in severe combined immunodeficient (SCID) mice for continuous noninvasive in-vivo evaluation. We employed intravital microscopic techniques to monitor effective microvascular permeability, functional vascular density, blood flow rate and leukocyte flux repeatedly over 16 days. Oxytetracyclin and v. Kossa/v. Giesson staining was performed to quantify the calcification process in vivo and in vitro.
Development of a hematoma surrounding the defect area was the initial event, which was accompanied by a significant increase in microvascular permeability and blood flow rate. With absorption of the hematoma and vessel maturation, permeability decreased continuously, while vascular density and tissue perfusion increased. Histological evaluation revealed that the remodeling of the substantial defect prolonged the in-vivo monitored calcification process.
The size of the initial substantial defect correlated positively with increased permeability, suggesting improved release of permeability-inducing cytokines. The unchanged permeability in the control group with boiled bones and a substantial defect corroborated these findings. The adaptation to increasing metabolic demands was initially mediated by increased blood flow rate, later with increasing vascular density through increased tissue perfusion rate. These insights into the sequence of microvascular alterations may assist in the development of targeted drug delivery therapies and caution against the use of permeability-altering drugs during bone healing.
[Show abstract][Hide abstract] ABSTRACT: Mechanisms regulating angiogenesis are crucial in adjusting tissue perfusion on metabolic demands. We demonstrate that overexpression of nerve growth factor (NGF) in brown adipose tissue (BAT) of NGF-transgenic mice elevates both mRNA and protein levels of vascular endothelial growth factor (VEGF) and VEGF-receptors. Increased vascular permeability, leukocyte-endothelial interactions (LEI), and tissue perfusion were measured using intravital microscopy. NGF-stimulation of adipocytes and endothelial cells elevates mRNA expression of VEGF and its receptors, an effect blocked by NGF neutralizing antibodies. These data suggest an activation of angiogenesis as a result of both: stimulation of adipozytes and direct mitogenic effects on endothelial cells. The increased nerve density associated with vessels strengthened our hypothesis that tissue perfusion is regulated by neural control of vessels and that the interaction between the NGF and VEGF systems is the critical driver for the activated angiogenic process. The interaction of VEGF- and NGF-systems gives new insights into neural control of organ vascularization and perfusion.
[Show abstract][Hide abstract] ABSTRACT: The appropriate surgery for curable squamous cell cancer (SCC) of the esophagus is discussed controversially.
Transthoracic esophagectomy (TTE) with radical en-bloc-lymphadenectomy was performed in 79/120 patients (66%). Due to severe comorbidity, 41/120 patients (34%) underwent less traumatizing transhiatal esophagectomy. Lymph nodes were stained using mAb BER-Ep4.
pN0 status was found in 54 patients (45%) and pN1 status in 66 patients (55%). In the pN0 subgroup, 30 out of 54 patients (55.6%) had occult tumor cells in lymph nodes detected with BER-Ep4. pN1 patients had additional BER-Ep4 positive cells in histopathologically negative lymph nodes in 41 out of 66 patients (59.2%). Median disease-specific survival was 31.4 and 16.8 months for the transthoracic and transhiatal groups, respectively (P = 0.129). pN0 patients lived longer after transthoracic resection (P = 0.0349), and in the subgroup without lymph node micrometastases this effect was even stronger (P = 0.025). In contrast, in pN0 patients with nodal microinvolvement, TTE did not entail a survival benefit when compared with the transhiatal group (P = 0.333).
TTE results in improved outcome in the absence of lymph node micrometastases. Poor survival in patients with lymphatic micro-dissemination indicates systemic disease and the need for adjuvant treatment.
No preview · Article · Jun 2006 · Journal of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: The processes of osteogenesis, bone remodelling, fracture repair and metastasis to bone are determined by complex sequential interactions involving cellular and microcirculatory parameters. Consequently studies targeting the analysis of microcirculatory parameters on such processes should mostly respect these complex conditions. However these conditions could not yet be achieved in vitro and therefore techniques that allow a long-term observation of functional and structural parameters of microcirculation in bone in vivo at a high spatial resolution are needed to monitor dynamic events, such as fracture healing, bone remodelling and tumor metastasis.
We developed a bone chamber implant (femur window) for long-term intravital microscopy of pre-existing bone and its microcirculation at an orthotopic site in mice preserving the mechanical properties of bone. After bone chamber implantation vascular density, vessel diameter, vessel perfusion, vascular permeability and leukocyte-endothelial interactions (LEIs) in femoral bone tissue of c57-black mice (n=11) were measured quantitatively over 12 days using intravital fluorescence microscopy. Furthermore a model for bone defect healing and bone metastasis in the femur window was tested.
Microvascular permeability and LEIs showed initially high values after chamber implantation followed by a significant decrease to a steady state at day 6 and 12, whereas structural parameters remained unaltered. Bone defect healing and tumor growth was observed over 12 and 90 days respectively.
The new femur window design allows a long-term analysis of structural and functional properties of bone and its microcirculation quantitatively at a high spatial resolution. Altered functional parameters of microcirculation after surgical procedures and their time dependent return to a steady state underline the necessity of long-term observations to achieve unaltered microcirculatory parameters. Dissection of the complex interactions between bone and microcirculation enables us to evaluate physiological and pathological processes of bone and may give new insights especially in dynamic events e.g. fracture healing, bone remodeling and tumor metastasis.
Preview · Article · Oct 2005 · Journal of Orthopaedic Research
[Show abstract][Hide abstract] ABSTRACT: Functional properties of tumour vasculature influence the process of metastasis and play a role in generating a heterogeneous metabolic microenvironment, which contributes to genetic instability and inefficiency of tumour therapies. Morphological and functional properties of tumour vasculature may vary from tumour onset to late-stage disease. The aim of this study was to identify the dynamic alteration in tumour microcirculation in a chronic observation model. Invasively-growing, non-disseminating, green fluorescent protein transfected, human bone marrow derived endothelial cells, were implanted into cranial windows of severe combined immunodeficient mice. Intravital fluorescence microscopy was performed over a period of 85 days to measure permeability, leucocyte-endothelial interaction (LEI) and tissue perfusion rate as functional parameters. Vessel density, branching pattern and scanning electron microscopy were monitored as morphological parameters. Concordant with an increasing count of transendothelial pores, the results show that the initial event following tumour cell implantation was a significant increase in the permeability of pre-existing vessels. The variations in newly formed vessels were characterised by sequentially-occurring functional and morphological alterations with the development of characteristics typical of tumour vessels, such as increased count of trifurcations and variation in vessel calibre by more than 100%. In parallel with the increasing vessel volume per area, the tissue perfusion rate increased until day 61. It is concluded from the step-specific sequential functional and morphological alterations that the efficiency of adjuvant therapies depends not only on their intrinsic efficiency but also on the timing of their initiation.
No preview · Article · Jun 2005 · European Journal of Cancer