Raising awareness about chronic intestinal pseudo-obstruction (CIPO): a case report showing CIPO as initial manifestation of atypical seronegative systemic sclerosis.

Only few case studies address pseudo-obstruction, a disorder - which often frustrates clinicians and patients due to an unclear diagnosis and limited therapeutic options. Thus, the aim of this paper is to investigate a relevant case concerning a patient presenting with symptoms of acquired chronic intestinal pseudo-obstruction (CIPO). After one year of extensive diagnostic tests and unsuccessful treatment with prokinetics, the patient underwent a subtotal ileocolectomy. The histology of the intestinal specimen revealed continuous atrophy and fibrosis mainly within the circular, inner muscle layer of muscularis propria of the ileum and colon. Even though serum markers were lacking, a subsequent skin biopsy showed signs of scleroderma supporting an initial diagnosis of intestinal involvement in systemic sclerosis. Despite treatment with steroids and methotrexate, the increasingly emaciated patient died. In conclusion, there is a bias against the publishing of pseudo-obstruction studies, in particular, due to the obscure underlying causes. To raise awareness of this problem, we call for clinicians to systematically generate comprehensive data about patients presenting these symptoms.

[Adenocarcinoma of the esophagogastric junction: prognostic factors and results of primary surgery]. / Ergebnisse der primär chirurgischen Therapie beim Adenokarzinom des ösophagogastralen Ubergangs.

INTRODUCTION: The incidence of adenocarcinoma of the esophagogastric junction (AEG) is increasing worldwide, and classification systems and resection procedures are being controversially discussed. METHODS AND PATIENTS: We report on 225 AEG patients undergoing primary resection in our unit (1986-2000) with a special focus on perioperative morbidity, mortality, and long-term prognosis under consideration of the AEG type (Siewert classification) and operative procedure performed (subtotal esophagectomy with proximal gastric resection in AEG I, total gastrectomy with distal esophageal resection in AEG II and AEG III). RESULTS: Types I, II, and III carcinomas were found in 32%, 42%, and 26% of the patients, respectively, with R(0) resections in 65%, 69%, and 51% ( P=0.039). The overall 5-year survival rates were 29%, 31%, and 14% ( P=0.068), respectively; in R(0)-resected patients, they were 40%, 41%, and 27% ( P=0.771). In univariate analysis, the TNM classification ( P<0.001), R classification ( P<0.001), and tumor stage ( P<0.001) were relevant prognostic factors. In multivariate analysis, only the R classification ( P=0.003), LN ratio ( P=0.012), and N stage ( P=0.027) were independent prognostic factors. In 35 of 177 patients resected with curative intent, R(0) resections could not be achieved, mainly because of residual tumor in the circumferential plane (22/35=63%). Only in 37% of cases (13/35) was the R(1) situation due to exclusive positive oral or aboral resection margins. Therefore, in only 7% of all patients resected with curative intent (13/177) did the question arise of whether the R(1) resection could have been avoided by a different surgical approach. Surgical, pulmonary, and cardiac complications were found in 33%, 26%, and 10%, respectively. The mortality within 30 days was 4%. CONCLUSIONS: Failure of R(0) resection in patients treated with curative intent is mostly caused by residual tumor in the circumferential plane. Therefore, different surgical approaches with varying oral and aboral resection margins are of minor importance for reducing the frequency of R(1) resections. Downstaging of tumors by neoadjuvant treatment may increase the R(0) resection rate.

Expense and benefit of neoadjuvant treatment in squamous cell carcinoma of the esophagus.

BACKGROUND: The effectiveness of neoadjuvant treatment (NT) prior to resection of squamous cell carcinoma of the esophagus (SCCE) in terms of prolonged survival has not been proven by randomized trials. Facing considerable financial expenses and with concerns regarding the consumption of the patient's remaining survival time, this study aims to provide rationales for pretreating resection candidates. METHODS: From March 1986 to March 1999, patients undergoing resection for SCCE were documented prospectively. Since 1989, NT was offered to patients with mainly upper and middle third T3 or T4 tumors or T2 N1 stage who were fit for esophagectomy. Until 1993, NT consisted of chemotherapy. Since that time chemoradiation has also been applied. The parameters for expense and benefit of NT are costs, pretreatment time required, postoperative morbidity and mortality, clinical and histopathological response, and actuarial survival. RESULTS: Two hundred and three patients were treated, 170 by surgery alone and 33 by NT + surgery. Postoperative morbidity and mortality were 52% to 30% and 12% to 6%, respectively (p = n.s.). The response to NT was detected in 23 patients (70%). In 11 instances (33%), the primary tumor lesion was histopathologically eradicated. Survival following NT + surgery was significantly prolonged in node-positive patients with a median survival of 12 months to 19 months (p = 0.0193). The average pretreatment time was 113 +/- 43 days, and reimbursement for NT to the hospital amounted to Euro 9.834. CONCLUSIONS: NT did not increase morbidity and mortality. Expenses for pretreatment, particularly time and costs, are considerable. However, taking into account that the results are derived from a non-randomized study, patients with regionally advanced tumor stages seem to benefit, as seen by their prolonged survival.

Long-term results following different extent of resection in chronic pancreatitis.

BACKGROUND/AIMS: To evaluate, whether the indication related varying extent of resection in chronic pancreatitis has a predictable impact on long-term outcome. METHODOLOGY: One hundred and twenty-six patients consecutively underwent surgery for chronic pancreatitis from March 1987 to September 1997. Three treatment categories were defined: Pancreatoduodenectomy, duodenum-preserving resection and drainage procedures, and left-sided pancreatectomy. Main outcome measures were late mortality, pain scores preoperatively and at follow-up, body-weight change, percentage of insulin dependent diabetes, patient's and physician's satisfaction with surgery. RESULTS: Forty-one patients underwent pancreatoduodenectomy, 59 drainage procedures, and 26 left-sided pancreatectomy, respectively. Hospital mortality was 1 (2.4%), 4 (6.8%), and 1 (3.8%) (P = NS), totaling 4.8%. After an average follow-up of 5.2 years, late mortality was 10 (24.4%), 9 (15.3%), and 4 (15.4%) (P = NS) for a total of 23 (18.3%). Two patients (1.6%) died of unsuspected pancreatic cancer. Three patients (2.4%) had to be reoperated upon for pain relapse. The mean pain score was 8.8 preoperatively and 2.1 at late follow-up and not different among groups. Body-weight gain averaged 3.0, 4.0, and 3.4 kg, with no significant differences. Percentage of insulin dependency in all patients rose from 14% prior to surgery to 30% at reevaluation, and was very similar in all treatment categories. CONCLUSIONS: The different kind and level of invasiveness of the surgical procedures did not significantly influence the late outcome. High rates of late mortality and deterioration of endocrine function are to a greater extent sequelae of comorbidity and the progression of the underlying pancreatic disease.

[Utilization of multimodal therapy concepts in stomach carcinoma in Germany]. / Anwendungspraxis multimodaler Therapiekonzepte beim Magenkarzinom in Deutschland.

INTRODUCTION: In view of disappointing results after surgery alone multimodal therapeutic regimes are used to improve long-term prognosis in locally advanced gastric carcinomas. In presence of many reports about encouraging results ("down staging", improved R0-resection rates) but simultaneously missing evidence of efficiency of neoadjuvant therapies in respect to long-term survival (large randomized multicenter trials do not exist until today) and the herewith related uncertainties, we started an inquiry among many surgical units with the intention to evaluate the clinical practice of multimodal treatment for gastric cancer patients in Germany today. METHODS: In a questionnaire (3/99) we asked among 97 surgical units (41 university hospitals, 56 big community hospitals) in Germany for the management of gastric cancer patients with special interest to practice and state of adjuvant and neoadjuvant therapeutic strategies. Further we analyzed all resected gastric cancer patients (1986-1995) without neoadjuvant treatment in advanced stage of disease (pT3/4NxMx; stage III/IV (UICC'92) in respect to R0-resection rate and long-term prognosis (Kaplan-Meier). RESULTS: Overall feedback amounted to 78% (76/97) and was higher in university hospitals (90%) than in big community hospitals (70%). Today, neoadjuvant therapies are of more interest than adjuvant therapeutic regimes. But also neoadjuvant therapy is only used in 32% as a rule (in 16% with, in 16% without study conditions). 25% of all surgical units do not employ any neoadjuvant therapy in locally advanced gastric cancer until today. In all other surgical units neoadjuvant treatment is performed more individually and sporadically (43%) only in some patients. Neoadjuvant therapies are practiced by haematooncologists in 50%, gastroenterologists in 32% and surgeons in 27%. The predominant neoadjuvant therapeutic strategy is chemotherapy alone (84%). Many surgical units in Germany are interested to participate in a multicenter trial with more interest in neoadjuvant than adjuvant therapy. 185 of 309 resected gastric cancer patients (60%) were classified as stage IIIa, stage IIIb or stage IV patients. R0-resection rate of these advanced gastric cancer patients amounted to 37%; only 24% of them survived 5 years or more. CONCLUSIONS: Considering the missing evidence that multimodal therapies are able to prolong long-term survival in advanced gastric cancer patients, its use without study conditions is questionable. Conclusions, taken from data of clinical trials regarding carcinomas of the esophagus and esophagealgastric junction, are inconsistent in respect to long-term prognosis and results are not transferable to gastric carcinomas. A prospective randomized multicenter trial in advanced gastric cancer patients is of great importance. Following our data, in Germany a high readiness to participate in the forthcoming EORTC-study is present.

[Surgical technique and outcome in pancreatic carcinoma]. / Chirurgische Technik und Ergebnisse beim Pankreaskarzinom.

Surgical treatment of ductal adenocarcinoma of the pancreas is considerably influenced by the delicate retroperitoneal position of the gland with close contact to major mesenteric vessels, lymphatics and nerve structures as well as by the unfavourable tumor biology including high affinity towards nerve tissue and early systemic spread. Based on these preconditions, kind and extent of resective measures have to be discussed with special care. Total pancreatectomy to improve radicality has been abandoned because of exaggerated early and late mortality and morbidity. The principle of distal gastric resection as part of the classic Whipple operation was shown to be oncologically not effective. It seems to be justified only if the tumor reaches the duodenopancreatic angle. Resection of the mesenteric vein is technically feasible with acceptable mortality, but leads to unfavourable survival rates since the respective lesions mostly are in an advanced stage. Extensive tissue clearance around the mesenteric vessels did not improve survival, but led to intractable diarrhoea in up to 76% of the cases. Concerning 114 patients resected for pancreatic head cancer in the own department actuarial 5-year survival was 6%. There was no significant difference whether classic Whipple (3%) or pylorus preservation (8%) was applied. None of the node positive patients survived more than 4 years. In contrast, those with negative nodes achieved 29% 5-years survival (p = 0.0059). Following 26 resections of the left pancreas for ductal carcinoma non of the patients survived more than 2 years. Results of the recent literature and the own experience are suggestive to believe that node positive stages won't benefit from extensive surgery. Therefore anatomical resection including the peripancreatic lymph node compartment is sufficient to preserve the chance for cure in early stages. Nowadays preservation of the stomach is the standard technique during pancreatoduodenectomy, which is, provided a perioperative mortality of less than 5%, accepted also as best palliation in suitable patient of advanced stages.

[Stomach saving duodenopancreatectomy. Indications and contraindications. The most important surgical steps]. / Die magenerhaltende Duodenopankreatektomie. Indikation und Kontraindikation. Die wichtigsten operativen Schritte.

Discussion on pylorus-preserving pancreatoduodenectomy (PPPD) in case of ductal adenocarcinoma is controversal. Aim of the present study was the comparison of survival in patients resected by the classic Whipple operation (Whipple) or the pylorus-preserving procedure. From April 1986 to June 1998 all patients operated for proven diagnosis of ductal pancreatic cancer were documented prospectively concerning patient's characteristics, kind of surgery, complications and histopathological staging according to the UICC-classification of 1992. During the observation period 100 patients underwent pancreatoduodenectomy, 38 cases as Whipple, 62 as PPPD. Average of age was 59.9 +/- 10.3 years without significant differences. Mortality was 6.0% in total, 5.5% post Whipple, and 6.5% post PPPD. Eighty-three percent of the resected specimen were node positive. The median survival time was 9.9 and 10.5 months, 5-year survival 2.6% and 10%, respectively without significant differences. Actually, only node positive patients reached 5-year survival. Even better survival figures following PPPD than after classic Whipple procedure make the pylorus-preserving procedure the standard operation in ductal cancer of the pancreatic head. Distal gastric resection is only mandatory in case of tumor involvement of the duodenopancreatic angle. Since only node negative cases survived 5 years, extensive surgery exceeding anatomical pancreatic head resection does not appear to be beneficial.

[Risks of radical treatment in pylorus preserving duodenopancreatectomy in ductal carcinoma]. / Zum Radikalitätsrisiko der pyloruserhaltenden Duodenopankreatektomie beim duktalen Carcinom.

Between 1986 and 1993 fifty-two patients with ductal adenocarcinoma of the pancreatic head underwent pancreatoduodenectomy, 34 in a standard Whipple technique (Whipple), 18 since 1990 preserving the pylorus (PPPD). Operating time was significantly longer for Whipple compared to PPPD (5.5 +/- 1.4 vs. 3.8 +/- 1.0; p < 0.01). Postoperative morbidity (32 vs. 56%) resulted to 50% after PPPD of early postoperative delayed gastric emptying. Hospital mortality was 6% vs. none, respectively. Histopathologic workup of 28 node positive Whipple specimens revealed node involvement in only 11% along the stomach (1) or the pyloric region (2), but in these cases tumors had obviously close relation to the gastric outlet as the reason to chose Whipple. Actuarial survival was very similar in both groups, being 41 vs. 53% at one year, 13 vs. 18% at two years, and only 3.3% at five years for the whole cohort. In conclusion distal gastric resection in Whipple's procedure in ductal carcinoma is oncologically not effective. There is no hazard for survival relating to the preservation of the pylorus. Therefore PPPD as the technically less expensive and for nutritional status more beneficial operation should be the procedure of choice also for this type of tumor.

Inflammatory islet damage in patients bearing HLA-DR 3 and/or DR 4 haplotypes does not lead to islet autoimmunity.

The hypothesis was tested that islet autoimmunity is induced by ongoing islet cell destruction in subjects with susceptibility genes HLA-DR 3 and/or DR 4. Sixty-one patients with confirmed chronic pancreatitis were analysed, 30 of whom expressed HLA-DR 3 and/or DR 4. Electron microscopy studies in 10 patients showed that the inflammatory process also affected islets, as recognisable from islet cell lysis, intrainsular fibrosis and immune cell infiltrates. None of the sera tested contained any of three markers of islet autoimmunity, ICA, IAA or GAD antibodies. A correlation was seen between the loss of exocrine function, as determined by the ALTAB-test, and of beta-cell function, as determined by the C-peptide response to i.v. glucagon. However, there was no preferential loss of beta-cell function in patients with HLA-DR 3 and/or DR 4. We conclude that islet cell destruction occurs during chronic pancreatitis, but does not trigger islet autoimmunity, even in the presence of HLA-DR 3 and/or DR 4.

[Effect of resection or duct drainage on glucose stimulated beta cell function in chronic pancreatitis]. / Einfluss von Resektion oder Gangdrainage auf die glukosestimulierte beta-Zellfunktion bei chronischer Pankreatitis.

Chronic pancreatitis (CP) leads to deterioration of the endocrine pancreatic function by fibrotic destruction. The aim of the present study was to investigate whether resection or duct drainage in patients with CP would have a direct impact on the pancreatic beta cell function. An intravenous glucose tolerance test (IVGTT) was performed before, after and in some cases 3 months after operation in ten patients each of whom had been treated by either resection or duct drainage. Three patients undergoing pancreatic resection for cancer served as controls. Beta cell function was assessed by glucose elimination (K-values), insulin and C-peptide response. K-Values in patients with CP were not significantly influenced after resection (1.93 +/- 0.78/2.13 +/- 0.72; n.s.) or drainage (1.26 +/- 0.47/1.54 +/- 0.58; n.s.) but reduced in all three tumor patients (2.23 +/- 0.55/1.23 +/- 0.43). The initial insulin response [microU/ml] in CP patients was also not altered after resection (19.7 +/- 17.3/16.0 +/- 18.2; n.s.) or after drainage (16.7 +/- 16.5/13.0 +/- 9.0; n.s.), whereas all three resected tumor patients showed reduced values (42.9 +/- 15.7/17.5 +/- 3.8). Stimulated C-peptide synthesis [ngmin/ml] was not substantially lowered in patients resected for CP (90.5 +/- 85.6/73.8 +/- 48.9; n.s.) or in the drainage group (121.3 +/- 67.5/98.0 +/- 57.2; n.s.), but this parameter was decreased in every tumor patient postoperatively (157.8 +/- 66.9/125.1 +/- 69.6). Resection in patients with chronic pancreatitis did not inevitably result in loss of beta cell function. Parenchyma-preserving drainage procedures had no measurable advantage in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)

Cold storage preservation of pancreatic tissue prior to and after islet preparation in a dog autotransplantation model.

Utilizing an intrasplenic canine islet autotransplant model, the effects of cold storage preservation on pancreatic tissue prior to and after collagenase dispersion were examined. A control series, in which freshly retrieved and prepared tissue was transplanted, yielded a 75% success rate (6/8). In contrast, when the pancreas was stored in modified silica gel filtered plasma (SGF I) for 24 hr, no autotransplant was successful (0/6). However, when the islet tissue was prepared following pancreatectomy and then stored in a mannitol-containing modification of SGF (SGF III), autotransplantation was successful in 83% (5/6) after 24 hr of preservation and in 60% (3/5) after 48 hr of preservation. Similarly, the islet tissue was stored in a hyperkalemic hydroxyethyl starch solution (HES) and this was successful in 20% (1/5) after 24 hr of preservation and in 50% (1/2) after 48 hr of preservation. Cold storage preservation techniques for the pancreas prior to islet isolation need to be refined, but dispersed islet-enriched pancreatic tissue can be successfully maintained at 4 degrees C for up to 48 hr prior to transplantation in dogs using established pancreas preservation solutions.

A simple method of canine pancreatic islet isolation and intrahepatic transplantation.

Clinical pancreatic islet transplantation has been impeded by the inability to isolate an adequate mass of functional tissue that will ameliorate diabetes. A simplified method of canine islet isolation was developed that allowed for either intrasplenic or intrahepatic transplantation. Following total pancreatectomy, parenchymal digestion was accomplished by intraductal collagenase perfusion and stationary incubation. The digested tissue was dispersed by filtration through a steel mesh (400 microns), washed, and separated on a discontinuous dextran density gradient. Enhanced islet tissue (2-4 ml) was recovered from the uppermost interface of the gradient and autotransplanted. The islet isolation procedure was tested in two series of dogs undergoing either intrasplenic or intrahepatic engraftment. Immediate and sustained normoglycemia (plasma glucose less than 200 mg%) was obtained in 5 of 8 dogs (63%) in the intrasplenic group and 6 of 8 dogs (75%) in the intrahepatic group. The mean fasting plasma glucose concentration 2 weeks after transplantation was 102.8 +/- 6.4 mg% in the intrasplenic group and 103.3 +/- 8.4 mg% in the intraportal group. The mean IVGTT K-values 2 weeks after transplantation were -1.41 +/- 0.35% and -1.21 +/- 0.13%, respectively. On the basis of insulin content, the islet yield was 33.0 +/- 3.7% of the total pancreas in the intrasplenic group and 33.0 +/- 3.1% in the intrahepatic group. Islet mass was enhanced 10.2 +/- 1.5 and 20.0 +/- 6.2 fold, respectively, on the basis of insulin/amylase ratios. The success rate in this canine model compared favorably with previously published results from other laboratories.(ABSTRACT TRUNCATED AT 250 WORDS)

Successful transplantation of canine islets of Langerhans after 24 hours cold-storage.

Utilizing the intrasplenic canine islet autograft model, it was possible to examine the effect of cold-storage of pancreatic tissue, both prior to and following dispersion, on functional outcome. A control group of dogs receiving freshly prepared autografts (n = 8) obtained durable euglycaemia in 75% of cases; the mean K value at two weeks being -1.70 (Standard Deviation (sd) = 0.06). In the first experimental group, animals (n = 8) were transplanted following 24 hours of whole pancreas cold-storage in silica gel fractionated plasma (SGF) using intraductal perfusion prior to preservation. None of these animals obtained euglycaemia; the transplanted material having a significantly reduced insulin content compared with controls (p = 0.0006). In the second experimental group, animals (n = 6) were transplanted following 24 hours of dispersed pancreatic tissue storage in SGF. This resulted in an 83% incidence of durable euglycaemia; the mean K value at two weeks being -1.60 (sd = 0.3). The glucose decay curve improved with time in this group and at three months the mean K value was -2.00 (sd = 0.38); this value being significantly superior to that of the control animals (K = -1.34, sd = 0.34, p less than 0.05). We conclude that while storage of the whole pancreas prior to islet isolation remains problematic, it is possible to reliably preserve dispersed pancreatic tissue for 24 hours by simple cold-storage, as assessed by the functional outcome of intrasplenic autografting in the dog model. These findings have important clinical implications.

Evaluation of the effects of opioid agonists and antagonists under a fixed-consecutive-number schedule in rats.

The effects of several opioid agonists and the opioid antagonist naloxone were examined in rats responding under a fixed-consecutive-number (FCN) schedule. Under this schedule, a reinforced response run consisted of responding eight or more times on one response lever, and then responding once on a second response lever. In one component of this schedule, an external discriminative stimulus signalled the completion of the response requirement on the first lever, whereas no stimulus change was programmed in the other. Morphine, l-methadone, U50488, ketocyclazocine, phencyclidine, and (+/-)N-allylnormetazocine decreased the percent of reinforced response runs (accuracy) under the FCN schedule without the external discriminative stimulus, but had no effect under the FCN schedule with the external discriminative stimulus. Naloxone and bremazocine, in contrast, had no effect on the accuracy of the discrimination under either FCN schedule. With the exception of bremazocine and U50488, which increased rates of responding at low doses, all drugs produced comparable decreases in rates of responding under both FCN schedules. During tests of antagonism, a 0.1 mg/kg dose of naloxone reversed completely the accuracy-decreasing effects produced by U50488 and morphine. The rate-decreasing effects of morphine and U50488 were reversed completely by a 0.01 and 1.0 mg/kg dose of naloxone, respectively. These results suggest that the addition of an external discriminative stimulus can modulate the disruptive effects of opioids, and that mu, sigma and some kappa agonists produce similar effects when evaluated under the FCN schedules.