Differential activation of afferent neuronal and inflammatory pathways during small bowel obstruction (SBO).

BACKGROUND: Small bowel obstruction (SBO) is a potentially life-threatening condition which may be caused by a variety of pathologies such as postoperative adhesions or malignant diseases. Little is known on alterations in gut physiology during SBO, although its comprehension is essential to improve treatment which may help to prevent subsequent organ failure prior to surgical resolution. We aimed to investigate afferent nerve sensitivity and intestinal inflammatory response during SBO to identify possible targets of treatment. METHODS: C57Bl6 mice were anesthetized, and a midline laparotomy was performed. A small bowel loop was ligated 5 cm proximal to ileo-cecal valve to induce SBO. Control animals received a sham midline laparotomy. SBO animals and controls were sacrificed after 3, 9, or 24 h (each n = 6). A dilated segment of small intestine located 1.5 cm oral to the ligature was prepared for multi-unit mesenteric afferent nerve recordings in vitro. Histological assessment of leukocyte infiltration was performed by myeloperoxidase (MPO). Pro-inflammatory cytokine expression was quantified by RT-PCR. Data are mean ± SEM. KEY RESULTS: Afferent firing to serosal 5-HT (500 µM) peaked at 3.9 ± 0.2 impulse/s 24 h after induction of SBO compared to 2.4 ± 0.1 impulse/s in sham controls (p < 0.05). Serosal bradykinin (0.5 µM) led to an increase in peak afferent firing of 5.3 ± 0.5 impulse/s in 24 h SBO animals compared to 3.5 ± 0.2 impulse/s in sham controls (p < 0.05). No differences in 5-HT and BK sensitivity were observed in 3 and 9 h SBO animals compared to controls. Continuous mechanical ramp distension of the intestinal loop was followed by a pressure-dependent rise in afferent nerve discharge that was reduced in 3 h SBO animals compared to sham controls (p < 0.05). MPO stains showed a rise in leukocyte infiltration of the intestine in SBO animals at 9 and 24 h (p < 0.05). Il-6 but not TNF-a gene expression was increased at 9 and 24 h in SBO animals compared to sham controls (p < 0.05). CONCLUSIONS & INFERENCES: Afferent nerve sensitivity is increased 24 h after induction of SBO. SBO led to a delayed onset intestinal inflammatory response. Inflammatory mediators released during this inflammatory response may be responsible for a later increase in afferent sensitivity. Agents with anti-inflammatory action may, therefore, have a beneficial effect during SBO and may subsequently help to prevent possible organ dysfunction.

The CR-POSSUM Risk Calculator Predicts Failure of Enhanced Recovery after Colorectal Surgery.

AIMS: To determine predictors of failed enhanced recovery after surgery (ERAS) in patients after elective colorectal surgery. METHODS: A cohort of 55 patients undergoing elective colorectal surgery was monitored prospectively. Perioperative care was based on a previously established protocol for ERAS. Pre-, intra-, and postoperative parameters were analyzed to elicit predictors of ERAS failure. ERAS failure was defined as prolonged hospital stay (> 7 days). The risk calculator CR-POSSUM was evaluated for its clinical utility. RESULTS: Body mass index (BMI) or the American Society of Anesthesiologists score (ASA) was not associated with ERAS failure on univariate analysis, but patients that failed ERAS were significantly older (64 y vs 54 y ; p = 0.023). Prolonged length of stay (> 7 days) was also associated with an open approach (p = 0.009), intraoperative nasogastric tube placement (p = 0.005), blood loss > 500 ml (p = 0.008), stoma formation (p = 0.006) and insertion of more than one intraabdominal drain during surgery (p = 0.005). Postoperative continuation of intravenous fluids (p = 0.027), reinsertion of urinary catheter (p = 0.045) and postoperative ileus (p = 0.020) were also strongly associated with delayed discharge on univariate analysis. After multivariate analysis the preoperative parameters CR-POSSUM score (p = 0.022), increasing BMI (p = 0.014) and preoperative albumin level (p = 0.031) were all independently associated with failure of ERAS. CONCLUSIONS: A variety of perioperative factors contribute to failure of ERAS in routine practice. CR-POSSUM can help to identify patients at risk for possible failure of ERAS. This may help to optimize avoidable factors, or accommodate those patients likely to require a longer post-operative stay.

The CR-POSSUM Risk Calculator Predicts Failure of Enhanced Recovery after Colorectal Surgery.

AIMS: To determine predictors of failed enhanced recovery after surgery (ERAS) in patients after elective colorectal surgery. METHODS: A cohort of 55 patients undergoing elective colorectal surgery was monitored prospectively. Perioperative care was based on a previously established protocol for ERAS. Pre-, intra-, and postoperative parameters were analyzed to elicit predictors of ERAS failure. ERAS failure was defined as prolonged hospital stay (> 7 days). The risk calculator CR-POSSUM was evaluated for its clinical utility. RESULTS: Body mass index (BMI) or the American Society of Anesthesiologists score (ASA) was not associated with ERAS failure on univariate analysis, but patients that failed ERAS were significantly older (64 y vs 54 y; p = 0.023). Prolonged length of stay (>7 days) was also associated with an open approach (p = 0.009), intraoperative nasogastric tube placement (p = 0.005), blood loss > 500 ml (p = 0.008), stoma formation (p = 0.006) and insertion of more than one intraabdominal drain during surgery (p = 0.005). Postoperative continuation of intravenous fluids (p = 0.027), reinsertion of urinary catheter (p = 0.045) and postoperative ileus (p = 0.020) were also strongly associated with delayed discharge on univariate analysis. After multivariate analysis the preoperative parameters CR-POSSUM score (p = 0.022), increasing BMI (p = 0.014) and preoperative albumin level (p = 0.031) were all independently associated with failure of ERAS. CONCLUSIONS: A variety of perioperative factors contribute to failure of ERAS in routine practice. CR-POSSUM can help to identify patients at risk for possible failure of ERAS. This may help to optimize avoidable factors, or accommodate those patients likely to require a longer post-operative stay.

Targeting the vasculature of visceral tumors: novel insights and treatment perspectives.

BACKGROUND: Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, describes a crucial process in tumor growth, disease progression, and metastasis. Therefore, the upcoming strategy of inhibiting tumor angiogenesis has generated different treatment modalities, which have been transferred into clinical practice in recent years. Currently, this concept is applied to target the vasculature of different visceral tumors and intensive clinical research has just started. MATERIALS AND METHODS: This review summarizes the modifications of systemic treatment of visceral tumors by targeting the vasculature in the past years. Moreover, novel targets and treatment strategies will be discussed to evaluate future directions. RESULTS: Leading antiangiogenic drugs combined with systemic chemotherapy have been applied with increasing success during the last years. Therefore, the concept of combining vascular targeting agents with established chemotherapeutic regimens has been increasingly adopted into the therapies of different visceral tumors. CONCLUSION: Targeting the vasculature of visceral tumors in combination with established standard tumor therapies includes major clinical potential for future therapy concepts.

Src tyrosine kinase inhibition suppresses lymphangiogenesis in vitro and in vivo.

PURPOSE: The close association of lymphatic and blood vessels and their coordinated development in vivo suggest that there are parallel mechanisms regulating hemangiogenesis and lymphangiogenesis. Here, we hypothesize that inhibition of the Src tyrosine kinase, apart from anti-hemangiogenic effects, results in a suppression of lymphangiogenesis. EXPERIMENTAL DESIGN: The ability of the Src kinase inhibitor PP2 to block Src in isolated lymphatic endothelial cells (LECs) was analyzed by Western Blot. The effects of PP2 on LEC proliferation, migration, and sprouting were assessed by MTT, Boyden chamber, and spheroid assays, respectively. The level of VEGF-C secreted by L3.6pl pancreatic carcinoma cells was measured by ELISA. For in vivo assessment of lymphangiogenesis, Src kinase inhibitor AZM475271 was used in mouse corneal micropocket and lymphangioma models. RESULTS: VEGF-C stimulation of isolated LECs led to an increased phosphorylation of Src kinase that was abrogated by PP2. Treatment with PP2 inhibited spheroid sprouting of LECs at even lower concentrations than suggested by the proliferation assay. Src inhibition significantly reduced the level of VEGF-C in L3.6pl supernatant. Treatment with PP2 also resulted in a significant reduction in the migratory activity of LECs. In vivo, Src inhibition reduced de novo formation of lymphangiomas and corneal neovascularization. CONCLUSIONS: Inhibition of Src kinase shows strong anti-lymphangiogenic activity in vitro and in vivo. Together with anti-angiogenic effects mediated by Src inhibition, this strategy may be attractive in the treatment of lymphatic and hematogeneous metastasis of cancer.

Blumgart anastomosis for pancreaticojejunostomy minimizes severe complications after pancreatic head resection.

BACKGROUND: Leakage from the pancreaticojejunostomy is the major cause of septic complications after partial pancreaticoduodenectomy. This study evaluated a new transpancreatic U-suture technique (Blumgart anastomosis, BA), which aims to avoid shear forces during knot-tying. METHODS: Using a before-after study design, BA was compared with a modified Cattell-Warren anastomosis (CWA). Two patient cohorts (CWA, 90; BA, 92), which were similar with respect to primary diagnosis, age, sex and American Society of Anesthesiologists score, were compared retrospectively. Dependent variables were surgical and overall morbidity and mortality after partial pancreaticoduodenectomy. RESULTS: Duration of operation (354 versus 328 min for CWA versus BA; P = 0.002), pancreatic leakage rate (13 versus 4 per cent; P = 0.032), postoperative haemorrhage (11 versus 3 per cent; P = 0.040), total surgical complications (31 versus 15 per cent; P = 0.011), general complications (36 versus 17 per cent; P = 0.005) and length of intensive care unit stay (median 5.4 versus 2.8 days; P = 0.015) were significantly reduced after BA. These effects were not related merely to an improvement over time. CONCLUSION: BA appears to be a fast, simple and safe technique for pancreaticojejunostomy. It might reduce leakage rates and surgical complications after partial pancreaticoduodenectomy.

Inhibition of Src tyrosine kinase reverts chemoresistance toward 5-fluorouracil in human pancreatic carcinoma cells: an involvement of epidermal growth factor receptor signaling.

Resistance to chemotherapy is believed to be a major cause of treatment failure in pancreatic cancer. Thus, it is necessary to explore alternative therapeutic modalities to overcome drug resistance in pancreatic cancer treatment. We tested the hypothesis that Src tyrosine kinase inhibition could augment the chemosensitivity of 5-fluorouracil (5-FU)-resistant human pancreatic cancer cells to 5-FU. As detected by MTT proliferation assay, propidium iodide and annexin V staining, a combination of 5-FU+Src kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) reflected the chemotherapeutic sensitivity and restored the 5-FU-induced apoptosis in 5-FU-resistant cells. Furthermore, when small-interfering RNA approach to silence Src gene expression was applied, the degree of 5-FU-induced apoptosis was increased in all cell lines independently of the chemoresistance status. Western blotting and RT-PCR analysis revealed that the expression of thymidylate synthase (TS) was higher in 5-FU-resistant cells, however, decreased significantly after pretreatment with PP2. Furthermore, the combination of 5-FU+PP2 decreased the 5-FU-induced activation of epidermal growth factor receptor (EGFR)-AKT pathway. Finally, PP2 in combination with 5-FU substantially decreased the in vivo tumor growth and inhibited distant metastases. Taken together, 5-FU chemoresistance can be reversed through indirect TS regulation by inhibiting Src tyrosine kinase. A potential mechanism of action of Src kinase inhibitors on 5-FU chemosensitivity might be linked to the inhibition of 5-FU-induced EGFR-AKT activation.

[Endoscopic Therapy of Early Colorectal Cancer (pT1) - A Prospective Study]. / Prospektive Studie zur endoskopischen Therapie des kolorektalen pT1-Karzinoms.

INTRODUCTION: In a prospective study initiated in 1982, we have been investigating the question as to whether - and if so, which - pT1 carcinomas of the colorectum can be treated exclusively via the endoscope. METHOD: In the period between February 1, 1982 and April 30, 2001, a total of 5,470 polyps were removed endoscopically at the Medical Department I of the Klinikum Ludwigsburg. Among these lesions, a total of 144 (2.6 %) pT1 carcinomas were found in 141 patients. We were able to follow 120 patients with 123 pT1 carcinomas over a mean follow-up period of 46 months (range: 1-60). In low-risk situations (definitive removal in healthy tissue, G1-G2, no lymphatic involvement), endoscopic treatment alone usually represented sufficient treatment. In high-risk cases (removal in healthy tissue uncertain or negative, and/or lymphatic vessel involvement, and/or G3/G4), subsequent surgical resection was carried out. RESULTS: 64 cases were classified as high-risk, 59 as low-risk. Nevertheless, 9 patients with 10 low-risk carcinomas were submitted to surgery (young age, patient's own request). In none of these 10 cases was residual tumour or lymph node metastasis detected in the surgical specimen. 47 patients with 49 low-risk carcinomas were treated solely by endoscopic polypectomy using the diathermy snare, and 45 patients with 47 carcinomas remained recurrence-free during the follow-up period. In a single case, a local recurrence was detected 2 months after polypectomy and underwent curative resection. In another case, peritoneal carcinosis with tumour infiltrating into the colon developed 8 months after initial treatment; this, however, was most probably a recurrence of a previously operated carcinoma of the uterus. Among the high-risk cases, 10 were not submitted to surgery on account of advanced age and/or rejection of an operation by the patient; all remained recurrence-free. Among the surgically treated high-risk carcinomas, 3 surgical specimens contained residual tumour, while 2 revealed a lymph node metastasis. In our group of patients, no tumour-related mortality was seen among endoscopically treated patients. DISCUSSION: In the light of the fact that the reported mortality rate associated with open surgery for colorectal carcinoma is 3 % as compared with about 1 % risk of lymph node metastasis and 0,1 % mortality rate for the endoscopic modality, endoscopic removal of a pT1 tumour in a low-risk situation followed by appropriate surveillance can be considered as adequate treatment.

Transplantation of H-2Kb-transgenic adrenocortical cells in the mouse having undergone an adrenalectomy: functional and morphological aspects.

BACKGROUND: A new model of cellular adrenocortical transplantation after bilateral adrenalectomy in the mouse was established. This model was used to study the effects of the expression of the transgenic MHC class I molecule H-2K(b) (Kb) on graft survival and morphologic features, corticosterone secretion, and the possibility of tolerance induction in the recipient. METHOD: A single cell suspension of purified adrenocortical cells was grafted under the kidney capsule of B10.Br (H-2k) mice having adrenalectomies. Syngeneic, fully MHC-mismatched, and MHC class I-incompatible Kb-transgenic mice served as donor strains. To analyze graft function, urinary excretion and serum levels of corticosterone were monitored over 100 days. Tolerance induction in the graft recipients of Kb-transgenic and third party skin grafts was tested on day 50 after adrenocortical transplantation. Histological sections of the adrenocortical grafts were obtained on day 100. RESULTS: Recipients of syngeneic and Kb-transgenic grafts displayed pretransplant corticosterone levels on days 20, 50, and 100 and ACTH-stimulated serum corticosterone levels similar to those of controls on day 100 after adrenocortical transplantation. In contrast, in recipients of fully MHC-mismatched grafts, corticosterone excretion was significantly reduced. In this group, 4 of 7 mice did not survive. Syngeneic skin grafts survived indefinitely in recipients of syngeneic and Kb-transgenic adrenocortical grafts, whereas Kb-transgenic and fully MHC-mismatched skin grafts were acutely rejected. Tissue sections of the adrenocortical grafts revealed vascularized cell conglomerates in syngeneic and Kb-transgenic grafts without infiltrations of mononuclear cells. Furthermore, a differentiation similar to adrenocortical organization was partly found. CONCLUSION: In conclusion, a model of cellular adrenocortical transplantation was established. The results show that syngeneic transplantation resulted in physiological corticosterone levels early after transplantation, whereas fully MHC-incompatible grafts were rejected. Recipients of Kb-transgenic grafts showed unimpaired adrenocortical function, but did not tolerize toward Kb-transgenic skin grafts. Possible mechanisms include a local immunomodulatory effect of glucocorticoids secreted by the graft and a low immunogenicity of the relatively small numbers of transplanted cells.

Behaviorally conditioned immunosuppression using cyclosporine A: central nervous system reduces IL-2 production via splenic innervation.

Bi-directional interactions between the central nervous system (CNS) and immune system are demonstrated by the modification of immune function using behavioral conditioning. However, the mechanisms by which the CNS achieves conditioned immunomodulation are still in question. Here, we report that the immunosuppressive effects of cyclosporine A (CsA) can be behaviorally conditioned in rats using saccharin as a gustatory conditioned stimulus. The conditioned effects were compared to control groups that received CsA paired with water (sham-conditioned), CsA injection on test days (CsA-treated), and unhandled rats (untreated). In conditioned animals, the mitogen-induced lymphocyte proliferation in the spleen is significantly suppressed, and the survival time of heterotopic heart allografts prolonged. These effects are paralleled by conditioned inhibition of IL-2 and IFN-gamma synthesis by splenocytes. Furthermore, the CNS-induced immunosuppression is mediated neuronally and not via the blood, since the conditioned reduction of proliferation and cytokine production is completely abrogated after surgical denervation of the spleen. Thus, during conditioning, the CNS learns to reinstate at demand a CsA-like immunosuppression via splenic innervation. This might be used as a supportive therapy for controlling immune functions.

A fatal case of Listeria endocarditis in a man following his tending of goats suggests an epidemiological link which is not supported by the results.

A man died in endocarditis due to listeriosis in the late autumn. He had been looking after two goats during the summer. Listeria monocytogenas was isolated from a rectal swab from one of the goats. The goat faeces isolate and the human blood isolate were of identical serovar. The two isolates, however, were shown to be different by multilocus electrophoretic enzyme analysis and ribotyping, as well as by biotyping. Thus, these results do not support the hypothesis that the man was infected by the goat.

Completion thyroidectomy in 131 patients with differentiated thyroid carcinoma.

OBJECTIVE: To evaluate the prognostic factors that influence survival and recurrence after "completion" thyroidectomy (removal of the total thyroid remnant after diagnosis of carcinoma has been made in a specimen that was incompletely excised for a benign condition). DESIGN: Open study. SETTING: Teaching hospital, Germany. SUBJECTS: 131 Patients (65 with papillary and 66 with follicular thyroid cancer) who underwent completion thyroidectomy after primary subtotal resection. INTERVENTIONS: Indications for further operation were: tumour stage worse than pT1 ( n = 116), tumour stage pT1 and the suspicion of persistence of the tumour (n = 13), and incompletely resected tumour (n = 2). Multivariate analysis by Cox's proportional hazards model. MAIN OUTCOME MEASURES: Recurrence, development of metastases, and length of survival. RESULTS: Patients who underwent their completion thyroidectomies within six months of the primary operation had significantly fewer recurrences, fewer lymph node metastases, fewer haematogenous metastases and survived significantly longer than those in whom the second operation was delayed for longer than six months. The age at the time of diagnosis and the stage of the tumour influenced survival, whereas sex and type of tumour did not. CONCLUSION: Completion thyroidectomy as soon as possible after incomplete resection of the tumour may improve prognosis in differentiated thyroid cancers the stage of which is worse than pT1 or in patients whose recurrent tumour is diagnosed at follow-up.

[The value of fine needle puncture in adrenal gland tumors]. / Stellenwert der Feinnadelpunktion bei Nebennierentumoren.

UNLABELLED: The value of fine needle biopsy (FNB) in adrenal masses was investigated in 33 patients presenting with such masses. Representative material was obtained 18 times from 19 patients with a history of tumour. 4 of them were diagnosed to be genuinely benign and 14 to be genuinely malignant. Further representative material was obtained 13 times from 14 patients with incidental findings of adrenal masses. The material gained by puncturing was classified correctly as benign in 9 cases, and twice it was considered benign although the tumours later proved malignant. In one case a clinically not suspected malignant lesion was detected by FNB, while in another case a malignant lesion was suspected by FNB, whereas a benign tumour was proven by means of surgery. The share of malignant diagnoses corresponded with the size of tumour, ascertained by the application of ultrasound or CT. The rate of malignant adrenal masses, which were found incidentally, increased from 7 cm onwards; however, the rate of malignant adrenal masses obtained from patients with a history of tumour increased distinctively already from 4 cm onwards. From 11 patients out of 33, adrenal tissue was obtained and classified as benign lesion (adenoma), although, by means of FNB and the conditions for reasons of method, a well differentiated carcinoma cannot be excluded. CONCLUSION: FNB is indicated for non-functioning tumours examined in patients with a history of tumour, furthermore, for incidental findings of the size between 4-6 cm. A diagnostic approach to adrenal masses is suggested.

Endoscopic polypectomy and management of colorectal adenomas with invasive carcinoma.

BACKGROUND AND STUDY AIMS: Invasive carcinoma is found at histology in 2-5% of colorectal polyps removed under flexible endoscopy. The aim of this study was to confirm that histologically complete endoscopic polypectomy under favorable low-risk conditions is sufficient therapy for pT1 carcinoma, while tumors at or close to the margin of the polypectomy, and histological high-risk criteria, require surgical resection with lymphadenectomy. PATIENTS AND METHODS: Eighty-six patients with 87 pT1 carcinomas underwent polypectomy within a twelve-and-a-half-year period. Further treatment prospectively followed the above guidelines. The follow-up was documented. RESULTS: A local tumor residue was found in 5 of 34 patients who had undergone surgical resection for doubtful or incomplete polypectomy. Two patients were found to have nodal disease in the surgical specimen, only one of them harboring a high-risk carcinoma. Two further patients with high-risk carcinomas had tumor progression, despite postpolypectomy resections without local tumor residue or lymph-node infiltration, and died. One patient had a local tumor recurrence on follow-up endoscopy eight weeks after doubtfully complete polypectomy. He underwent resection, and had no further recurrence. No further manifestations of invasive carcinoma occurred after complete polypectomy of 42 patients with low-risk carcinomas. CONCLUSIONS: This study supports the view that complete endoscopic polypectomy is an adequate therapy for low-risk carcinoma: A modification of the follow-up regimen, with less frequent endoscopic controls, is justified.

[Benign chondroma of the pancreas]. / Benigner Knorpelzelltumor im Pankreas.

Fragments of a puncture cylinder were obtained from a pancreas tumour, using the ultrasound-guided fine-needle puncture. The tumour appears as an echo-poor, homogeneous structure suggesting good delineation against the adjoining tissue. Histological examination of the punch cylinder revealed a chondroma of the pancreas. Clinical and clinical pathology examinations (lipase, alpha-amylase, glucose, CEA, CA 19-9 in serum) were inconspicuous. Chondroma of the pancreas does not require specific treatment.

Isolation of Listeria monocytogenes from goat cheese associated with a case of listeriosis in goat.

Listeria monocytogenes was isolated from the brain of a goat, which was euthanized due to listeriosis. A few weeks later a similar subtype of L. monocytogenes was isolated from an on-farm manufactured fresh cheese which did not contain any milk from the goat which had suffered from listeriosis. A similar subtype was also found on 1 of the shelves in the refrigerator where cheeses were stored. Prior to the onset of listeriosis, 1 fresh cheese had been made of milk from the actual goat, which may have excreted L. monocytogenes in her milk. Thus, the cheese made of this milk may have contaminated the shelves in the refrigerator which then has served as a Listeria reservoir for new cheeses during several weeks.