[Score prediction of metastatic risk in Gastrointestinal Stromal Tumours (GIST)]. / Entwicklung eines Malignitätsscores zur Vorhersage der Metastasierungswahrscheinlichkeit Gastrointestinaler Stromatumoren (GIST).

The purpose was to generate a score targeted at the metastatic risk potentially reflecting oncogenic activation in Gastrointestinal Stromal Tumours (GIST). In 41 patients size and location of the primary, mitotic index, initial symptoms, and histological appearance were rated with 0 to 1 or 2 points. The course of the disease was recorded as incidental, symptomatic, locally recurrent, with peritoneal dissemination, or with hepatic spread. The parameters tumour size (p < 0.001), mitotic index (p < 0.001), localisation of the primary (p < 0.001) and symptoms (p < 0.05) correlated with the course of the disease. This correlation was highly significant (p << 0.0005) when the overall score was applied, the median being 0 in incidental, 3 in symptomatic, 4 in locally recurrent, 4.5 in peritoneal, and 5 points in hepatic spreading GIST. Results were compared with those of an established risk stratification. The sensitivity and specificity of a score > 4 for the occurrence of liver metastases were 100 and 73.5 % compared with 85.7 and 82.4 % for a high risk profile according to Franquemont's classification. The results indicate the ability of routinely recorded data to predict the metastatic outcome of GIST.

Surgery for cystic lymphangioma in Gorlin-Goltz syndrome.

INTRODUCTION: We present a case of three major lymphomesenteric cysts in a female patient with known basal cell nevus syndrome (BCNS or Gorlin-Goltz syndrome). DISCUSSION: Although those cysts have been reported to appear in this syndrome, the exact prevalence is not known. In this case, the patient suffered from severe and recurrent abdominal pain due to bowel obstruction. CONCLUSION: By causing severe symptoms, cystic lymphangiomas are an important complication of the BCNS despite of their seldom occurrence. Surgeons confronted with intraabdominal masses in a patient with BCNS should always be aware of this manifestation of the disorder and plan interdisciplinary operations.

Chemokines in human colorectal carcinoma.

BACKGROUND: Chemokines (CKs) may promote antitumor immunity in cancer, act as tumor growth factors, influence metastatic spreading or angiogenesis. The purpose of this study was to investigate whether CK expression is altered in colorectal carcinomas compared to normal mucosa and to elucidate its possible clinico-pathological implications. MATERIALS AND METHODS: The levels of CCL2 (MCP-1), CCL4 (MIP-1beta), CCL5 (RANTES), CXCL 1 (GRO-alpha), CXCL 5 (ENA-78) and CXCL 8 (IL-8) were investigated in 10 colorectal carcinomas and their corresponding normal mucosa by the use of ELISA. RESULTS: All CK analyzed, with the exception of CCL5 (RANTES), were expressed at a significantly higher level in malignant tissue. CONCLUSION: Therapeutic studies in colon carcinomas should, therefore, focus more on the neutralization of CKs than on their application.

Significance of total vascular exclusion for hepatic cryotherapy: an experimental study.

BACKGROUND: In the liver, efficacy of cryosurgical ablation of tumors located near the retrohepatic vena cava is impaired by the heat-sink effect. This could be overcome by total vascular exclusion (TVE) of the liver. In this study, the effect of TVE on cryosurgical ablation of liver tissue close to the retrohepatic vena cava was investigated with regard to the extent of the cryolesion and complications arising from necrosis of the caval wall. METHODS: Of a total of 28 pigs, 14 underwent cryotherapy with TVE compared to 14 without TVE, both involving the vena cava. 7 animals in each group were subjected to one freeze cycle and 7 in each group to two freeze cycles. Temperatures in the cryolesion were monitored and cryolesions were documented sonographically. Laboratory parameters were determined pre- and postoperatively. Follow-up was 14 days. Morphology, extent of the cryolesion, damage to the vena cava and complications were assessed after autopsy. RESULTS: With TVE, freezing rates were increased and cryolesions were significantly larger than without TVE. Transmural necroses of the vena cava with complete necrosis of the intima occurred significantly more frequently after TVE. Macro- and microscopically, the damage to the caval wall was considerably more marked after cryotherapy under TVE but in all cases the continuity of the vessel wall remained intact. There were no ruptures, thrombosis, or strictures of the vena cava. CONCLUSIONS: The combination of cryotherapy and TVE increases the effectiveness of cryoablation in the liver involving the retrohepatic vena cava without any severe vascular complications occurring in the pig.

[Esophageal carcinoma: non-surgical therapy]. / Osophaguskarzinom--Nicht-chirurgische Therapie.

Esophageal carcinoma is one of the most common cancers in the world. There is a rising incidence of adenocarcinoma of the esophagus in Western countries. The present standard of care of patients with early tumors (Tis-T1 N0-N1 M0) is surgery and there is no role for chemo- or radiotherapy. Surgical treatment of stage II patients with locally resectable tumors is associated with poor survival figures due to an increase of regional and distant lymph node metastases. Adjuvant chemotherapy should be used only in the setting of clinical trials. The role of neoadjuvant chemo-radiotherapy in patients with resectable tumors is controversial. There is also evidence that some patients with a complete response after chemo-radiotherapy do not have a further benefit from surgical treatment. Therefore, the appropriate application of these varied therapeutic interventions should be performed at specialized centers. The role of chemotherapy and radiation is now established in locally advanced inoperable disease. How best to deliver these modes of therapy has yet to be defined. Prospective randomised trials are the only way to define the best therapeutic strategies for the different subgroups of patients with esophageal carcinoma. Progress with newer chemotherapy agents, optimal radiotherapy protocols and innovations are likely to improve responses to combination treatments, but may more importantly limit associated toxicity. Future trials should also assess quality of life indices as end points, that are of particular importance in populations with a median survival of approx, one year. Patients with stage IVb esophageal carcinoma have a life expectancy of less than six months and palliative teatment strategies should primarily aim at the improvement of tumor related symptoms and the maintenance of nutrition.

Hepatic cryotherapy involving the vena cava. Experimental study in a pig liver model.

Liver tumors located near the retrohepatic vena cava are often considered nonresectable. For these patients cryoablation could be a therapeutic option. In this study the safety and efficacy of hepatic cryosurgery involving the retrohepatic vena cava were investigated. Cryolesions involving the vena cava were created in 26 pigs. Follow-up was 24 h and 14 days. The extent of the cryolesion, damage to the vena cava and complications were assessed after autopsy. The cyronecrosis extended into the wall of the vena cava in 81% of the animals. All animals had an uneventful recovery without any complications such as ruptures of the vessel, thrombosis or pulmonary embolism. Microscopically elastic and collagenous fibers of the cava wall remained intact. The continuity of the vessel wall was conserved. In conclusion, the safety and efficacy of cryosurgical treatment involving the retrohepatic vena cava were shown in a pig model.

[Liver metastases in colorectal carcinoma. With complete resection healing is possible]. / Lebermetastasen bei kolorektalem Karzinom. Bei kompletter Resektion ist die Heilung möglich.

Surgical treatment of liver metastases from colorectal carcinoma can achieve 5-year survival rates of up to 40%, and 10 year survival rates of up to 20%, making resection the only potentially curative treatment option. This applies, however, only when metastatic disease is confined to the liver and when complete removal of the metastases is possible. Patients with liver metastases from non-colorectal primaries--with the exception of the rare neuroendocrine tumors--are not usually candidates for surgery.

[Postoperative peripheral neuropathies in general surgery]. / Postoperative periphere Neuropathien in der Allgemeinchirurgie.

INTRODUCTION: Postoperative nerve lesions beyond the operative area, the so called positioning traumas are considered uncommon in general surgery. But they can have serious consequences for the patient and the surgeon, including forensic sequelae. The objective of this work was to describe the incidence, pattern, risk factors and course of postoperative neuropathies in general surgery and to identify indicators to prevent these complications. METHODS: Based on neurologic records we reviewed all postoperative peripheral neuropathies that occurred in the Department of General Surgery of the University Hospital Freiburg in the time period from January 1979 to December 1990. Lesions that occurred as a direct operative effect were excluded. RESULTS: In 35 patients 50 nerve lesions were observed, representing an incidence of 0.12% of all operations during this time period. Most frequently lesions of the n. peroneus occurred, followed by the n. ulnaris, n. cutaneous femoris lateralis and n. medianus. Nerve lesions were observed in every body position and as early as after 15 min. Postoperative nerve lesions have a favorable prognosis. DISCUSSION: Nerve lesions caused by positioning can occur during any operation with any duration in general surgery. They should be avoided by thorough and careful positioning. Also the patient must be informed about the possibility of nerve lesions caused by the positioning.

Expression and activity of mitogen activated protein kinases in human colorectal carcinoma.

BACKGROUND: Mitogen activated protein kinases (MAPKs) play a central role in the regulation of both cell growth and differentiation. They are involved in signal transduction of oncogenes and growth factors. The role of MAPK in colonic carcinoma is unknown. AIMS: To establish whether the expression and activity of p42/44 MAPKs are altered in colorectal tumours as compared with normal mucosa. METHODS: The expression and activity of p42/p44 MAPK were investigated in 22 colorectal carcinomas, four adenomas, and the corresponding normal colorectal mucosa by the use of western blotting, immunoprecipitation, and in vitro kinase assays. RESULTS: After immunoprecipitation with an antibody specific for p42 MAPK, we found significant inactivation of p42 MAPK in colonic carcinomas as well as in adenomas, whereas most sample pairs showed only minor differences in p42 MAPK expression. Investigation of MAPK with an antibody capable of detecting both p42 and p44 MAPK showed a slight but significant decrease in p44 MAPK content in malignant tissues. With this antibody, only minor alterations in MAPK activity and no correlation with p42 MAPK activity were found. CONCLUSIONS: Inactivation of p42 MAPK could be associated with colonic carcinogenesis.

Adrenal-sparing surgery for phaeochromocytoma.

BACKGROUND: Adrenalectomy is the current treatment for phaeochromocytoma. Consequently, patients with bilateral adrenal phaeochromocytoma become steroid dependent. An adrenal-sparing surgical technique was introduced in 1985. The results of this treatment have been reviewed. METHODS: Since 1985, 39 patients with adrenal phaeochromocytoma (16 men and 23 women, aged 10-76 years) have been treated. Thirty-three patients had unilateral and six had bilateral phaeochromocytomas. Seven of the former 33 had a contralateral adrenal tumour resected previously. All 39 patients were re-evaluated biochemically and clinically for ipsilateral recurrence. RESULTS: Adrenal-sparing surgery was performed successfully in 37 of the 39 patients. In one, adrenal-sparing resection was impossible anatomically and total adrenalectomy was necessary. Another patient with bilateral tumours had retroperitoneal haemorrhage and became steroid dependent. None of the remaining 12 patients who had bilateral adrenal surgery required steroid replacement. Adrenocortical function was normal in eight and mildly impaired in two of the ten patients who had evaluation by adrenocorticotrophic hormone stimulation. After a mean follow-up of 73 months, one patient with von Hippel-Lindau disease developed a recurrence in the ipsilateral adrenal gland. Genetic testing revealed that 26 of the 39 patients, including half of those with a unilateral tumour, had hereditary phaeochromocytoma. CONCLUSION: Adrenal-sparing surgery is safe and effective, and may become the treatment of choice in patients with hereditary phaeochromocytoma.

Raf-1 kinase, epidermal growth factor receptors, and mutant Ras proteins in colonic carcinomas.

Epidermal growth factor receptors (EGFR) and ras mutations are known to play a significant role in controlling cell growth and tumor promotion. Both of them transmit mitogenic signals to the nucleus by activation of Raf-1 kinase. In this study, the expression of EGFR and mutant Ras proteins, and, for the first time, the expression, phosphorylation and kinase activity of Raf-1 kinase have been determined in paired samples of colorectal cancer and mucosa. The tumor and mucosa samples did not differ significantly with regard to Raf-1 kinase content and activity. A major difference between tumors and mucosa was found, however, in the phosphorylation of Raf-1. Most of the mucosa samples (13/20), but only 1/20 of the cancer samples, contained hyperphosphorylated Raf-1. EGFR were significantly (p = 0.0025) decreased in the tumors. The decreased phosphorylation of Raf-1 in colonic carcinomas could be the result of activation of Raf-1 phosphatases or inactivation of kinases phosphorylating Raf-1. New forms of treatment based on EGFR overexpression do not seem to be suitable for the majority of colonic cancers.

Autocrine growth stimulation of SW403 colon carcinoma cell line is caused by transforming-growth-factor-alpha-mediated epidermal growth factor receptor activation.

Results of recent studies indicate that some cultured human carcinoma cell lines are capable of proliferating autonomously in serum-free medium as a result of the synthesis and secretion of transforming growth factor alpha (TGF alpha). TGF alpha interacts with epidermal growth factor receptor (EGFR) and induces its activation. In an attempt to extend these observations, we evaluated TGF alpha-mediated autonomous growth and constitutive EGFR activation in the human adenocarcinoma cell line SW403. The cell line shows synthesis of EGF receptors and TGF alpha but not EGF, and exhibits constitutive phosphorylation of the 170-kDa EGFR. Use of blocking anti-EGFR monoclonal antibodies (mAb) inhibits autonomous growth of SW403 cells and leads to a significant reduction of receptor phosphorylation. The inhibitory effect of the blocking anti-EGFR mAb is reversible upon addition of TGF alpha. In contrast, autonomous proliferation of SW403 cells is not inhibited by addition of neutralizing anti-EGF mAb. Our findings suggest that the proliferation of cells of the human SW403 adenocarcinoma cell line is regulated by an autocrine TGF alpha loop and that this regulatory pathway can be interrupted by using anti-EGFR mAb.

Expression of GM-CSF and a functional GM-CSF receptor in the human colon carcinoma cell line SW403.

Only little is known about the expression of a functional granulocyte-macrophage colony-stimulating factor receptor (GMR) and its ligands in human colon carcinoma cell lines. To obtain more information on this subject, we investigated the human colon carcinoma cell line SW403, and we were able to demonstrate the constitutive synthesis of a 85-kDa GMR in SW403 cells. After stimulation with 10% fetal calf serum, GM-CSF transcripts were expressed as well. The incubation of SW403 cells with GM-CSF resulted in an intensive down-regulation of the activity of the interferon-gamma-receptor gene, which could be reconstituted by simultaneous addition of an anti-GM-CSF antibody. GM-CSF induced an activation of tyrosine-phosphorylated protein kinases with molecular weights in the range of 30 to 210 kDa, but it had no effect on the DNA synthesis of SW403 cells.

[Therapy and follow-up of gastroesophageal chemical burns]. / Therapie und Verlauf gastroösophagealer Verätzungen.

We report a retrospective analysis of 61 patients admitted during the years 1974 to 1992 after having recently swallowed a corrosive agent. Within 24 hours, the localisation, severity and extent of the injury had been determined by endoscopy. In 13 patients the injury was restricted to the oropharynx, and in 48 it involved esophagus, stomach and duodenum. Fourteen had sustained a second degree injury, and 16 a third degree injury. Out of five patients with third degree injuries who were treated by operation within the first three days, two survived. Two patients operated upon for complications after 10 days of conservative treatment died. The total mortality was 21%, but 56% for those who had received a third degree injury. Thirteen patients developed a stenosis (27% of those with gastroesophageal lesions). Esophageal strictures were dilatated with bougies, but stomach stenoses were treated by resection. Of the 12 patients treated by dilatation, 4 sustained perforations and 4 of them were free of symptoms for a considerable period of time (more than 4 years).

Expression of gastrin, gastrin/CCK-B and gastrin/CCK-C receptors in human colorectal carcinomas.

To investigate further the presence of an autocrine proliferative loop involving gastrin in colorectal carcinomas and to clarify the receptor responsible, 102 human colorectal carcinomas and 10 hepatic metastases were investigated for the expression of the genes encoding gastrin, the gastrin/CCK-B receptor and the gastrin/CCK-C receptor. Levels of RNA expression were assayed by RNase protection assay. In addition, gastrin/CCK receptors on crude membranes of tumour tissue were assayed by radioligand binding. High-affinity gastrin/CCK-B receptors were not detected in any of the carcinomas investigated, whereas in 36% low-affinity binding was observed, consistent with the expression of the gastrin/CCK-C receptor. RNase protection assay detected the RNA for the gastrin/CCK-B receptor in 11% of the carcinomas investigated, whereas the RNA for the gastrin/CCK-C receptor was demonstrated in 75% and the RNA for gastrin in 86% of the carcinomas investigated. These results confirm the recent demonstration of progastrin fragments in colorectal carcinomas. One possible explanation for progastrin expression is that such progastrin fragments may participate in an autocrine proliferative loop. The receptor involved in this loop is more likely to be the low-affinity gastrin/CCK-C receptor rather than the gastrin/CCK-B receptor, which is rarely expressed in colorectal carcinomas.

Radiation enteropathy.

PURPOSE: Radiation enteropathy presents a complex clinical picture which varies from case to case. Diagnosis and treatment require a thorough knowledge of the natural history of the condition and of the complications which are to be expected. PATIENTS AND METHODS: The pathogenesis, clinical picture, diagnosis and treatment of radiation damage to the gut are described. The progress of 90 patients operated on in the Chirurgische Universitätsklinik Freiburg is retrospectively evaluated. RESULTS: Haemorrhage, vomiting, diarrhoea and, occasionally, perforation are the signs of acute radiation enteropathy, which appears weeks or months after radiotherapy. Except for perforations, these can usually be treated conservatively. Chronic radiation enteropathy does not manifest itself until years after irradiation, with diarrhoea, obstruction and the development of fistulae. The acute ileus can often be relieved with decompression tubes. After localising the stenosis radiologically with a contrast medium, and improvement in the general condition, many cases require operative intervention. This usually consists of resection, the establishment of a bypass anastomosis or enterostomy. In 44% of the patients postoperative complications followed, with a mortality of 22%. The cause of the high complication rate is partly the poor general condition of the patient, and partly the radiation induced impairment in wound healing, which may lead to insufficiency of the anastomosis and the development of fistulae. CONCLUSIONS: The treatment of radiation enteropathy is a demanding task. Because of the high complication rate, it is generally wise to choose the least risky procedure.

[The value of CEA immunoscintigraphy for diagnosis of colorectal cancer and its metastases: results of a prospective study]. / Die Bedeutung der CEA-Immunszintigraphie für die Diagnostik kolorektaler Karzinome und ihrer Metastasen: Ergebnisse einer prospektiven Studie.

The importance of the CEA-immunoscintigraphy (IS; BW 431/26 Fa Behring) for the diagnosis of colorectal carcinoma and its metastases was determined in a prospective trial including 60 patients. The results were compared with results of the ultrasound, the CT-Scan and the Angio-CT. Patients suffered from a colorectal carcinoma (15), from a local tumor recurrence after bowel resection (10), from hepatic (39) and/or extrahepatic metastases (16). In 40 patients the diagnosis was confirmed by laparotomy. Regarding the detection of hepatic metastases the sensitivity and specificity of the Angio-CT were superior to the IS (0.86 and 0.63 vs. 0.78 and 0.45). Ultrasound and Angio-CT together revealed true positive results in 89.2%. The IS did not improve this rate. Regarding the detection of extrahepatic metastases the sensitivity and the specificity of the CT were slightly superior to the IS (0.59 and 0.87 vs. 0.47 and 0.28). However, the IS increased the rate of true positive results by 18.8% (US + CT 43.7%; +IS 62.5% true positive results). Due to these results the IS is not recommended as the method of choice to detect liver metastases. But in patients unfit for diagnostic laparotomy the IS may give additional information of the extrahepatic tumor stage.

[Serum gastrin level in patients with colorectal adenoma or carcinoma]. / Serumgastrinspiegel bei Patienten mit kolorektalem Adenom oder Karzinom.

During the last years interest has focused on the trophic effect of gastrin in colorectal carcinomas. Some reports indicated an increased serum level of gastrin in patients with colorectal adenomas or carcinomas. In a prospective study in 261 patients submitted to colonoscopy fasting serum gastrin concentrations were determined. 91 patients served as control, 89 patients had one or more adenomas, 55 patients suffered from a colorectal carcinoma, 17 had a benign, postoperative stenosis of the colon, and 9 had a chronic inflammatory bowel disease. All patients fulfilled the following criteria: No regular drug intake, no previous gastric or small bowel operation, no known ulcer disease, no abnormalities in serum calcium, creatinine, triglycerides, cholesterol and blood urea. Mean gastrin level was 86.63 +/- 23.8 pg/ml in the control, 84.57 +/- 25.1 pg/ml in the adenoma group and 84.6 +/- 24.4 pg/ml in the carcinoma group. No difference of serum gastrin levels were observed regarding sex, age, tumor stage and localisation.

Influence of gastrin, gastrin receptor blockers, epidermal growth factor, and difluoromethylornithine on the growth and the activity of ornithine decarboxylase of colonic carcinoma cells.

Polyamines are essential factors of cell growth and differentiation. Modulation of the cellular polyamine content by 2-difluoromethylornithine (DFMO) inhibiting ornithine decarboxylase (ODC), or by hormones inducing ODC, influences cell growth. Gastrin acts trophically on some colonic carcinomas and their growth is inhibited by gastrin receptor blockers. The mechanism of the trophic action of gastrin on colonic carcinomas is not known. In this study the effect of gastrin, gastrin receptor blockers, epidermal growth factor (EGF) and DFMO on growth and ODC activity of four human colon carcinoma cell lines (SW 403, SW 1116, LS 174 T and Lovo) was investigated. Growth and ODC activity of all cell lines were inhibited by DFMO. Growth of the SW 403 cell line was increased by gastrin and inhibited by the gastrin receptor blocker benzotrypte. The other cell lines did not respond to gastrin and the gastrin receptor blocker. In SW 403 cells ODC activity was increased by gastrin, and was also elevated after treatment with the gastrin receptor blocker. These in vitro results were confirmed by studies on tumours that developed from SW 403 cells in nude mice. Combination of benzotrypte and DFMO did not enhance the antiproliferative effect. EGF increased growth of SW 403 cells, but no induction of ODC activity was measured. LS 174 T cells were not stimulated by EGF. Medium replacement was the strongest stimulus of ODC activity in SW 403 cells already inducing ODC after 3 h. During cell culture ODC activity was high after seeding and decreased continuously with increasing cell density. These data suggest that gastrin induces ODC in gastrin-sensitive colonic carcinoma cells. DFMO appears to be a valuable antiproliferative agent in colonic carcinoma cells.