A rare cause of distal bile duct stenosis.

INTRODUCTION: In a patient with a distal bile duct stenosis a definite diagnosis could not be made preoperatively. DISCUSSION: The histologic evaluation of the surgical resection specimen revealed infiltration of the pancreatic head and the distal bile duct by breast tumor cells. CONCLUSION: The metastasis was the only tumor manifestation after mastectomy 12 years ago.

Adjuvant chemotherapy in stage III colon cancer with 5-fluorouracil and levamisole versus 5-fluorouracil and leucovorin.

BACKGROUND: Adjuvant chemotherapy for colon cancer has been established during the past decade. From 1990 until recently treatment with 5- fluorouracil (5-FU) and levamisole (LEV) lasting 12 months was recommended as standard treatment. At the initiation of this study in 1993 improvement of adjuvant therapy was expected by the modulation of 5-FU with folinic acid (FA). Therefore, we decided to perform a prospective randomized multicenter trial to compare standard 5-FU/LEV to 5-FU/FA for either 6 or 12 months. PATIENTS AND METHODS: Patients with stage III colon cancer after curative en bloc resection were randomized in 3 treatment groups: arm A (5-FU/LEV, weekly, 12 months), arm B (5-FU/FA, days 1-5, every 4 weeks, 12 months) and arm C (like B, 6 months). RESULTS: Between March 1993 and November 1997, 180 patients were randomized into the study, 155 were eligible for further evaluation. The interim analysis in November 2000 showed no significant difference for recurrence and disease-free survival in arm B and C, therefore the data from both 5-FU/FA treatment arms (B+C) were combined for comparison with 5-FU/LEV-treatment (A). Most pronounced toxicity in all treatment arms was mild nausea, loss of appetite and leukopenia. A tendency for more diarrhea and stomatitis was observed in arm B+C. After a median follow-up of 36.2 months no significant difference was seen for disease free survival (p = 0.9) and overall survival (p = 1.0). 3-year recurrence rates were 39.6% in arm A and 39.1% in arm B+C, 3-year survival rates amounted to 74.1% in arm A and 74.9% in arm B+C. CONCLUSION: Only a limited number of patients could be recruited in this study. The observed data support the results of other studies, which concluded that 6 months (or 12 months) treatment with 5-FU/FA is equivalent to 12 months treatment with 5-FU/LEV. Therefore the 6 months treatment with 5-FU/FA can be supported as standard for adjuvant therapy of stage III colon cancer.

Mutation analysis of replicative genes encoding the large subunits of DNA polymerase alpha and replication factors A and C in human sporadic colorectal cancers.

We examined cDNAs of the catalytic subunit of DNA polymerase alpha (185 kDa), the 70 kDa subunit of replication protein A (single-stranded DNA-binding protein) and the 140 kDa subunit of replication factor C for mutations. Surgical specimens from 12 patients with sporadic colon cancer and normal mucosae from the same patients were investigated. In addition, we analyzed 3 human colon cancer cell lines that exhibited defects in mismatch repair (DLD-1, HCT116, SW48) and 3 colon cancer cell lines without such a defect (HT29, SW480 and SW620). For detection of mutations, we used reverse transcription of mRNA, amplification of cDNAs by PCR, analysis of single-strand conformation polymorphism and DNA sequencing. Eleven colon cancers and 6 colon cancer cell lines were analyzed for DNA polymerase alpha. Only 2 silent point mutations were detected, in 1 colon carcinoma and in cell line HCT116. Two sequence alterations of the 70 kDa subunit of replication factor A were identified in 15 specimens (9 colon carcinomas and 6 cell lines). Colon carcinomas from 2 patients (CC5MA and CC25HN) exhibited an ACA-->GCA transition in codon 351, which caused a Thr-->Ala exchange. In carcinomas CC5MA and CC8MA, a TCC-->TCT (Ser-->Ser) transition in codon 352 was observed. The deviations in codons 351 and 352 occurred in both cancer tissues and normal mucosae, suggesting a genetic polymorphism. No mutation was found in the 140 kDa subunit of replication factor C from 16 specimens (10 tumors and 6 cell lines). Point mutations were identified in the p53 tumor-suppressor gene in 4 of the 6 colon cancer cell lines and 3 of the 8 carcinoma specimens. We did not find tumor-associated DNA sequence alterations that resulted in amino acid changes in the DNA replication genes analyzed. We infer that the scarcity of mutations found is due to stringent selection, eliminating functionally impaired replication proteins.

Effect of carnitine on muscular glutamate uptake and intramuscular glutathione in malignant diseases.

Abnormally low intramuscular glutamate and glutathione (GSH) levels and/or a decreased muscular uptake of glutamate by the skeletal muscle tissue have previously been found in malignant diseases and simian immunodeficiency virus (SIV) infection and may contribute to the development of cachexia. We tested the hypothesis that an impaired mitochondrial energy metabolism may compromise the Na+-dependent glutamate transport. A randomized double-blind clinical trial was designed to study the effects of L-carnitine, i.e. an agent known to enhance mitochondrial integrity and function, on the glutamate transport and plasma glutamate level of cancer patients. The effect of carnitine on the intramuscular glutamate and GSH levels was examined in complementary experiments with tumour-bearing mice. In the mice, L-carnitine treatment ameliorated indeed the tumour-induced decrease in muscular glutamate and GSH levels and the increase in plasma glutamate levels. The carnitine-treated group in the randomized clinical study showed also a significant decrease in the plasma glutamate levels but only a moderate and statistically not significant increase in the relative glutamate uptake in the lower extremities. Further studies may be warranted to determine the effect of L-carnitine on the intramuscular GSH levels in cancer patients.

Nerve irritation after laparoscopic hernia repair.

BACKGROUND: Between October 1992 and May 1996, 893 hernia repairs were performed at the Surgical Clinic in Mannheim: 448 (50%) using laparoscopy (TAPP-method) and 445 (50%) using the conventional anterior approach (Shouldice). MATERIALS AND METHODS: For this study, 723 (81%) of these repairs were followed up in a prospective trial of postoperative nerve irritations. RESULTS: The rate of nerve entrapment in the laparoscopic group was 4.2% (n = 19), and in the group that underwent conventional surgery 1.8% (n = 8). The genitofemoral nerve was affected with particularly high frequency (2%), and the ilioinguinal nerve and lateral cutaneous nerve of the thigh (LCNT) each was affected in 1.1% of the cases. CONCLUSIONS: Reduction in the number of clips used and careful attention to the anatomic nerve course during preparation and placement of mesh led to a significant reduction in the occurrence of nerve irritations. In the last 100 patients who underwent laparoscopic hernia repair, only one nerve lesion was seen.

Detection of mutations in the DNA polymerase delta gene of human sporadic colorectal cancers and colon cancer cell lines.

To test the hypothesis whether DNA polymerases acquire mutator properties during tumor development (mutator hypothesis), we examined DNA polymerase delta mRNA in 6 colon cancer cell lines (DLD-1, HCT116, SW48, HT29, SW480 and SW620) and 7 sporadic human colorectal cancers. For analysis we used amplification of cDNA by polymerase chain reaction, single-strand conformation polymorphism and sequencing techniques. In 5 of the cell lines, 9 mutations leading to changes of the amino acid sequence of DNA polymerase delta were detected. Most mutations were found in the cell lines DLD-1, HCT116 and SW48 for which defects in mismatch repair genes had been identified previously. In the majority of cases, wild type and mutated sequences were present. In 2 cell lines (HCT116 and SW48), a single-nucleotide deletion occurred at the same position. This resulted in a premature termination codon by which the DNA interaction domain of the enzyme was eliminated. Furthermore, sequence deviations were found in the tumor tissues of 4 colon cancer patients. Wild-type and altered sequences were present simultaneously. The deviations included missense mutations (2 cases) and silent mutations (2 cases). The missense mutations and one of the silent mutations were found in normal mucosa as well. In addition, the mutation clustered region of a tumor suppressor gene, often found to be defective in colon cancer, the adenomatous polyposis coli (APC) gene, was investigated in surgical specimens and cell lines. One carcinoma and 2 cell lines exhibited amino acid changes in both the DNA polymerase delta gene and in the mutation clustered region of the APC gene. Since most of the mutations detected in the DNA polymerase delta mRNA are likely to alter the structure of the protein, the enzyme is expected to be functionally impaired. In particular, copying fidelity might be decreased, thus contributing to the high mutation rate observed in colorectal cancer.

Immunization with virus-modified tumor cells.

Direct infection of tumor cells with viruses transfering protective or therapeutic genes-a frequently used procedure for production of tumor vaccines in human gene therapy-is often limited by the number of tumor cells that can reliably be infected, as well as by issues of selectivity and safety. In this review, we describe an efficient, selective, and safe way of infecting human tumor cells with a natural virus with interesting pleiotropic immune stimulatory properties, the avian paramyxovirus Newcastle disease virus (NDV). Advantages of this virus are its good cell-binding properties, its selective replication in tumor cell cytoplasm, which is independent of cell proliferation, and its relative safety. Most important for its use as an adjuvant in human cancer vaccine are its ability to introduce T-cell costimulatory activity, to prevent anergy induction, and to induce locally chemokines (eg, RANTES, IP-10) and cytokines (eg, interferon alpha, beta [IFN-alpha, beta] and tumor necrosis factor-alpha [TNFalpha]) that affect T-cell recruitment and activation. A further development consists of attachment-via NDV-derived hemagluttinin-neuraminidase (HN) membrane-anchoring molecules-of universal defined bispecific reagents such as T-cell-activating anti-CD28 antibodies. Finally, we summarize the status of our clinical studies with the autologous virus modified live cell vaccine (ATV)-NDV.

[Adjuvant radiochemotherapy with 5-FU and folinic acid in Dukes stage B and C rectum carcinoma: an interim analysis]. / Adjuvante Radiochemotherapie mit 5-FU und Folsäure beim Rektumkarzinom des Stadiums Dukes B und C: Zwischenanalyse.

In a prospective multi-institutional German adjuvant trial patients with curatively resected rectal cancer (Dukes B or C) were randomly assigned to receive postoperative radiotherapy (50.4 Gy) and either 12 or 6 cycles of 5-fluorouracil and medium-dose folinic acid. Our preliminary results of the interim analysis, based on 206 patients, indicate that this adjuvant therapy is well tolerated by the patients and a prolonged chemotherapy over 12 months has no advantage over 6 months of chemotherapy. The relatively high rate of tumor recurrence (30.7%) after a median follow-up of 29.3 months in this trial emphasizes the need for dose intensification planned for a further trial.

[Hormone inactive neuroendocrine tumors of the pancreas]. / Hormoninaktive neuroendokrine Tumoren des Pankreas.

During the past 10 years (1987-1996), 842 laparotomies were performed for pancreatic or periampullary neoplasms; in 25 patients (2.9%) a neuroendocrine tumor was diagnosed. In 19 of these 25 patients (76%) a non-functioning endocrine tumor and in 6 patients (24%) a hormone-active tumor (four insulinoma, one gastrinoma, one VIPoma) was found. Of 19 non-functioning neuroendocrine tumors, 14 were malignant. The resection rate of these malignant tumors was 78.6% (11 of 14; 3 resections were palliative); in comparison, the resection rate of ductal pancreatic carcinoma in our hospital was 28.1%. The probability of 5-year survival amounts to 73% after surgical resection in malignant endocrine tumors and to 19% in ductal pancreatic carcinoma (including palliative resections). As it is not always clear whether non-functioning endocrine tumors are benign or malignant, oncological resection is recommended. Adjuvant chemotherapy seems not to be necessary.

Quality-of-life after curative surgery for gastric cancer: a comparison between total gastrectomy and subtotal gastric resection.

BACKGROUND/AIMS: Quality-of-Life has become an increasingly important factor for long term survivors after surgery for gastric cancer. Quality-of Life also includes social and psychological aspects. Many gastric carcinomas are located in the distal two thirds of the stomach. In these cases, a subtotal gastric resection may be adequate if a proximal safety margin of 5 cm in intestinal type tumors according to Laurén and 10 cm in diffuse type cancers respectively can be achieved. On the other hand total gastrectomy "de principe" has been advocated for all gastric malignancies because of high local recurrence rates after subtotal resection. The aim of the present study was to assess the Quality-of-Life in long term survivors after resection for gastric cancer comparing subtotal gastric resection with total gastrectomy. METHODOLOGY: One hundred ninety-five patients were examined with the Gastrointestinal Quality-of-Life-Index (GLQI). Hard clinical data such as postoperative weight loss, frequency of daily meals and bowel emptying were evaluated. One hundred five patients were submitted for total gastrectomy and in 90 patients a subtotal gastric resection was performed. None of the patients had clinical, radiological or endoscopic evidence of recurrence. RESULTS: After subtotal gastric resection, patients achieved statistically significant better scores concerning disease/therapy-related symptoms, physical functions resulting in a better overall score (p < 0.02). Following subtotal resection, patients had a significantly lower weight loss compared to patients after total gastrectomy (p < 0.02), a smaller number of daily meals (p < 0.001) and a lower frequency of bowel emptying/day (p = 0.031). There was no statistically significant difference in emotional status or social activities showing a similar acceptance of disease and therapy in both groups. CONCLUSIONS: In those cases where an adequate proximal safety margin can be achieved by a subtotal gastric resection, this procedure is preferable to a total gastrectomy. However preservation of the gastric stump should never be allowed to compromise oncological radicality.

HLA class II expression in well differentiated thyroid carcinoma: correlation with clinicopathological features.

Lymphocytic infiltration and aberrant expression of HLA class II antigens on malignant thyroid epithelial cells are assumed to play a relevant role in the immune response against thyroid cancer. Aberrant expression of the HLA class II alpha and beta chains as well as number and distribution of tumor infiltrating lymphocytes were investigated in primary tumors (n = 54) and metastases (n = 4) of well differentiated thyroid carcinomas (follicular carcinoma: n = 26, papillary carcinoma: n = 28). The immunohistochemical findings were correlated with clinicopathological features. An aberrant HLA class II beta chain expression was detected in 9 (28%) papillary carcinomas and 4 (15%) follicular carcinomas. Three HLA class II beta chain positive papillary carcinomas and all follicular carcinomas were negative for the HLA class II alpha chain. All lymph node and distant metastases were negative for both HLA class II alpha and beta chain. Number and distribution of CD45R0+ lymphocytes significantly (p < 0.05, Fisher test) correlated with the aberrant HLA II antigen expression on tumor cells. There was also a significant correlation (p < 0.05, Fisher test) between an aberrant HLA II antigen expression and invasion of the vessels. No correlation was found between aberrant HLA class II expression and the occurrence of lymph nodes or distant metastases. Our findings indicate that the expression of HLA class II antigens on thyroid carcinoma cells is high in the step of invasive growth and that the local immune response towards the HLA class II antigens appears to prevent metastatic spread of HLA II positive tumor cells. There is evidence of different expression of HLA class II chains in follicular and in papillary thyroid carcinomas, which could be a further indicator that in these two subgroups of thyroid carcinomas different changes in the regulatory mechanisms of HLA class II antigen expression occur.

[Results of surgical therapy of stomach carcinoma in the elderly]. / Ergebnisse der chirurgischen Therapie des Magencarcinoms beim älteren Menschen.

In our hospital 35% of the patients undergoing resection for gastric carcinoma are over 70 years old. This group was divided into three age groups; clinico-pathological features, operative morbidity and mortality as well as long-term prognosis were compared with findings taken from a control group of subjects under 70 years old. No differences were noted in the distribution of the UICC stages and the incidence of early gastric cancer. The number of subtotal gastric resections was significantly higher in older patients. During the past 10 years the perioperative morbidity and mortality rates have decreased markedly and only minor differences in comparison with the control group have been recorded. However, the 5-year survival rate was significantly lower in the age group above 80 years old (13.7%) than in the control group (48.7%). Univariate analysis of prognostic factors showed the UICC stage, lymph node metastases, resection line involvement and the patient's age to be of significance. In contrast, in the multivariate analysis age was not of prognostic value.

The role of laparoscopy in the preoperative staging of pancreatic carcinoma.

Between January 1990 and December 1995, a total of 398 patients underwent laparotomy for pancreatic or periampullary carcinoma at the Surgical Clinic of Mannheim. The tumor was located in the pancreatic head in 290 patients (72.9%), in the body of the pancreas in 42 patients (10.6%), and in the pancreatic tail in 19 patients (4.7%). Forty-seven patients (11.8%) presented with periampullary carcinoma. The preoperative diagnostic workup included abdominal ultrasound, CT scan, endoscopic retrograde cholangiopancreatography, and angiography. One hundred seventy-two patients (43.2%) underwent a tumor resection, 150 (37.7%) had a palliative bypass operation, and 76 (19.1%) underwent only an exploratory laparotomy. Preoperative diagnosis had predicted unresectability in 66 (87%) of the patients who underwent exploratory laparotomy. In 76 patients the intraoperative findings showed an unresectable tumor, which was located in the head of the pancreas in 54 cases (71%), in the body of the pancreas in 17 (22.4%), in the tail region in four (5.3%), and in the periampullary region in one (1.3%). Local signs of unresectability were found in 47 patients (62%) and peritoneal or hepatic metastases in 29 (28.2%). Given that local inoperability can be reliably assessed only at laparotomy, this leaves just 29 (7%) of 398 patients who did not require palliation and whose signs of unresectability could possibly have been discovered by means of the laparoscopic approach. Laparoscopy (including laparoscopic ultrasound) should be used selectively in patients considered probably unresectable who do not require a palliative procedure immediately before the planned operation.

[Ultra-rapid magnetic resonance tomography: a quantum leap in preoperative hepatobiliary diagnosis?]. / Ultraschnelles Kernspintomogramm: Ein Quantensprung in der präoperativen hepatobiliären Diagnostik?

The recent improvements in magnetic resonance (MR) imaging using the new ultrafast echo-planar technique for diagnosis of hepatobiliary lesions are outstanding. Besides the detection and preoperative evaluation of benign and malignant hepatobiliary tumors, angiography and cholangiography can be simultaneously performed using the techniques of MR angiography or MR cholangiography. Looking ahead, further advantages such as three-dimensional image reconstruction, no X-ray exposure, and short examination time, this MR technique will become the preferred diagnostic procedure for evaluating hepatobiliary lesions.

[Geriatric tumor surgery--change in the patient sample]. / Geriatrische Tumorchirurgie--Wandel des Krankengutes.

The comparison of our surgical tumor patients over 65 years of age treated in 1973-1974 or 1993-1994 showed the following results: increased average age and more patients with a greater unfavorable preoperative risk profile, an increase in colorectal tumors, a decrease in gastric carcinomas, no changes in tumor stages, more frequent sphincter-preserving operations for rectal tumors, an increase in the curative resection rate, lower mortality and shorter hospital stays. A curative resection of a malignant tumor is justified in the majority of elderly patients and should be performed considering the post-operative quality of life.

[Results of colorectal carcinoma surgery in elderly patients]. / Ergebnisse der colorektalen Karzinomchirurgie des alten Patienten.

Between 1972 and 1995, 4434 operations for colorectal carcinoma were performed at the University Clinic of Mannheim. The increasing average age of the patients resulted in a higher lethality rate due to more emergency operations and concomitant failure of other organs. But the prognosis of patients over 70 years old can be compared with younger patients when hospital lethality is not considered. Thus the aim of treatment in older patients is also R0-resection, avoidance of emergency operations, optimum treatment of concomitant failure of other organs and multiple operations in extreme emergency cases.

Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma.

An active specific immunization (ASI) procedure with two types of autologous tumor cell vaccines (ATVs) is tested for adjuvant immunotherapy of resected colorectal carcinoma to provide preliminary information on local immunological skin responses, side effects, and 2-year survival rates. For vaccine preparation, the tumor-derived freshly isolated and cryopreserved cells were thawed, purified by Percoll density centrifugation, and depleted of tumor-infiltrating lymphocytes by immunomagnetic beads. After inactivation by 200 Gy, the cells of this ATV were either infected by Newcastle disease virus (NDV) or they were admixed with Bacillus Calmette Guérin (BCG) organisms. Vaccination was performed in the arm beginning 6-8 weeks after operation, three times at 2-week intervals. Of 57 patients that received ASI, 48 were treated by virus-infected ATV (ATV-NDV) and 9 were treated with the BCG-admixed vaccine (ATV/BCG). The mean value of delayed hypersensitivity skin reactions from ATV-NDV-treated patients was 18 mm for the first vaccination and 26 and 29 mm for the succeeding ones. Although the application of ATV-NDV was associated with only mild side effects, the ATV/BCG vaccine led to long-lasting ulcers and to more serious side effects. The 2-year survival rate obtained with ATV-NDV was 97.9%, whereas the survival rate with ATV/BCG was 66.7%. The mean survival of 661 patients from a historical control was 73.8%. These data suggest that the type and quality of the tumor vaccine for ASI treatment is important. The findings with ATV-NDV necessitate corroboration in a prospective, randomized controlled study.

Substrate balances across colonic carcinomas in humans.

To investigate the utilization of nutrients by malignant tumors in humans, the balances of energy-yielding substrates and amino acids across colonic carcinomas were assessed in 17 patients during surgery. Blood samples were taken from an artery and the main tumor-draining vein, which was also used for determining tumor blood flow (direct venous outflow technique). Additionally, the substrate exchange by peripheral tissues was studied (femoral arteriovenous differences, venous occlusion plethysmography). Mean blood flow was greater in the carcinomas than in the leg tissues (43.2 versus 2.5 ml/100 ml/min; P < 0.001). There was a negative correlation between tumor blood flow and tumor weight (r = -0.87; P < 0.001). Glucose net uptake and lactate release by the malignancies exceeded the peripheral exchange rates 30- and 43-fold, respectively (mean values different at P < 0.001). The molar ratio of lactate output to glucose consumption was 0.78 in the tumors and 0.48 in the leg tissues (P < 0.05). Regarding free fatty acid and ketone body balances, no significant tumor-periphery differences were noted. The carcinomas utilized branched chain amino acids and serine, while alanine and, in particular, ammonia were released in large amounts. Net glutamine retention was not consistently observed. It is concluded that the energy metabolism of human colonic carcinomas relies predominantly on glucose, with fat-derived calories making no appreciable contribution. The impaired nutritive perfusion of malignant tumors appears to favor glycolysis and to limit both glucose oxidation and glutaminolysis. The present study has shown that the procedure chosen for the assessment of trans-tumor substrate flux rates is a workable and valid model for analyzing metabolic balances across human colonic cancers in vivo.

Protein metabolism in human colon carcinomas: in vivo investigations using a modified tracer technique with L-[1-13C]leucine.

To quantify the protein anabolism of tumors it is not sufficient simply to determine the level of protein synthesis. The decisive factor is the net balance. This is the first attempt to establish this parameter in human tumors in vivo. Intraoperative tumor leucine/protein metabolism was studied in 15 patients with resectable malignant colon tumors using a balance model and L[1-13C]leucine as the tracer substance. Comparative measurements were also carried out simultaneously for peripheral tissue (forearm); in addition, protein kinetics parameters were established for the whole body using a proven two-pool model (with the same tracer as above). In view of the frequently conflicting data on amino acid metabolism in tumors, the tumoral and peripheral exchange rates of 20 amino acids were also determined. In tumors, essential and branched-chain amino acid uptakes were found to be 1.68 +/- 0.59 (SE) and 1.52 +/- 0.23 mumol/100 g tissue/min, respectively; in peripheral tissue there was overall an amino acid release [-0.11 +/- 0.06 and -0.05 +/- 0.04 mumol/100 g/min; in either case P < 0.01 (tumor versus periphery)]. Tracer analyses yielded a net retention for the tumors but a protein loss for peripheral tissue (8.941 +/- 3.113 versus -0.557 +/- 0.53 g/kg/24 h; P < 0.01) and for the whole body (-0.363 +/- 0.04 g/kg/24 h). The tumors were divided into two prognostic groups on the basis of their histology. Significant differences were found between the two groups in terms of the net retention rate for 10 amino acids, including leucine; retention was elevated in tumors with an unfavorable prognosis, possibly due to a higher amino acid requirement because of more rapid growth or for export processes (mucus production). The protein balance model used here has proved satisfactory for our purposes and could also be used to directly evaluate dietary measures (e.g., adjuvant parenteral nutrition in connection with chemotherapy).