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Chimeric antigen receptor (CAR) T-cell immunotherapies for solid tumors face critical challenges such as heterogeneous antigen expression. We characterized SSEA-4 cell-surface glycolipid as a target for CAR-T cell therapy. SSEA-4 is mainly expressed during embryogenesis but is also found in several cancer types making it an attractive tumor-associated antigen. Anti-SSEA-4 CAR-T cells were generated and assessed pre-clinicallyin vitroandin vivofor anti-tumor response and safety. SSEA-4 CAR-T cells effectively eliminated SSEA-4 positive cells in all tested cancer cell lines whereas SSEA-4 negative cells lines were not targeted.In vivoefficacy and safety studies using NSG mice and the high-grade serous ovarian cancer cell line OVCAR4 demonstrated a remarkable and specific anti-tumor response at all CAR-T cell doses used. At high T cell doses, CAR-T cell-treated mice showed signs of health deterioration after a follow-up period. However, severity of toxicity was reduced with delayed onset when lower CAR-T cell doses were used. Our data demonstrate the efficacy of anti-SSEA-4 CAR-T therapy; however, safety strategies, such as dose-limiting and/or equipping CAR-T cells with combinatorial antigen recognition should be implemented for its potential clinical translation.

Fibrinogen was purified by protamine-agarose chromatography from plasma from three patients after their submission to hospital due to acute myocardial infarction. The total amount of phosphate bound to fibrinogen and the concentration of fibrinogen was determined in samples withdrawn immediately after submission and after thrombolytic treatment. Streptokinase treatment almost totally removed circulating fibrinogen while recombinant tissue plasminogen activator spared much of it. In patients treated with streptokinase, the new circulating fibrinogen was homogeneous according to the single alpha-band seen after sodium dodecyl sulphate polyacrylamide gel electrophoresis analysis under reducing conditions, whereas fibrinogen from the recombinant tissue plasminogen activator-treated patient as well as healthy controls exhibited two alpha-bands in the 66-kDa region. The molar ratios of phosphate to fibrinogen of healthy controls and commercial fibrinogen were 0.82 (+/-0.04) and 0. 87 (+/-0.05), respectively. For two streptokinase-treated patients the degree of phosphorylation increased threefold from a normal range of 0.97 (+/-0.11) and 0.67 (+/-0.09) mol/mol fibrinogen before treatment to 3.33 (+/-0.32) and 1.86 (+/-0.17) mol/mol in newly formed fibrinogen on day 1. Recombinant tissue plasminogen activator treatment led to a smaller increase in phosphorylation, from 1.14 (+/-0.13) pretreatment to 1.65 (+/-0.11) after treatment on day 1. In conclusion we show in this report that after streptokinase treatment of patients with acute myocardial infarction, the new Aalpha-chain of fibrinogen was a homogeneous single 66-kDa band on sodium dodecyl sulphate polyacrylamide gel electrophoresis under reducing conditions and that the degree of phosphorylation of plasma fibrinogen was elevated, approaching the theoretical limit of 4 mol phosphate/mol fibrinogen.

The Vanadium/Lithium system has been the recent focus of ANL`s Blanket Technology Pro-ram, and for the last several years, ANL`s Liquid Metal Blanket activities have been carried out in direct support of the ITER (International Thermonuclear Experimental Reactor) breeding blanket task area. A key feasibility issue for the ITER Vanadium/Lithium breeding blanket is the Near the development of insulator coatings. Design calculations, Hua and Gohar, show that an electrically insulating layer is necessary to maintain an acceptably low magneto-hydrodynamic (MHD) pressure drop in the current ITER design. Consequently, the decision was made to convert Argonne`s Liquid Metal EXperiment (ALEX) from a 200{degrees}C NaK facility to a 350{degrees}C lithium facility. The upgraded facility was designed to produce MHD pressure drop data, test section voltage distributions, and heat transfer data for mid-scale test sections and blanket mockups at Hartmann numbers (M) and interaction parameters (N) in the range of 10{sup 3} to 10{sup 5} in lithium at 350{degrees}C. Following completion of the upgrade work, a short performance test was conducted, followed by two longer multiple-hour, MHD tests, all at 230{degrees}C. The modified ALEX facility performed up to expectations in the testing. MHD pressure drop and test section voltage distributions were collected at Hartmann numbers of 1000.

Integrating total quality management (TQM) into the strategic planning process of a multi-institutional health system is a high priority. Through the strategic plan, system leadership gives TQM concepts prominence and visibility and provides strategic directions for their implementation. The Sisters of Providence Health System recently developed an approach to integrating TQM into its System Strategic Plan. Implementation priorities include more formalized direction for TQM by the system board, intensive TQM educational programs, greater consistency of quality information and outcome measures, and more focused attention to patient needs.

The aim of this study was to evaluate the consequences of chronic pouchitis after restorative proctocolectomy for ulcerative colitis.Forty-two patients with chronic pouchitis underwent pouch endoscopy with biopsies after a median of 8.3 years of postoperative follow up. The pouchitis disease activity index (PDAI) was calculated. Morphological changes were recorded. Immunohistochemical analyses for cyclooxygenase 2 (COX-2), Ki-67 and p53 were performed, as was DNA flow cytometry. Endoscopy was also carried out in 10 patients without pouchitis and in nine healthy subjects.In patients with chronic pouchitis, the PDAI was 6 (standard error of the mean ± 4). Eighteen (43%) patients used continuous medication. The PDAI correlated positively with villous atrophy (P0.05). None of the pouch biopsies showed dysplasia. COX-2 immunostaining was detected in 35 (83.3%) patients with chronic pouchitis, in five (50%) without pouchitis, but in none of the normal controls. COX-2 expression correlated with mucosal atrophy (P0.01). In 15 (35.7%) of 42 patients with chronic pouchitis, Ki-67 immunostaining was increased, but no increase was observed in either control group (P0.002). No p53 immunopositivity was found, and DNA flow cytometry was normal in all pouches. One of the patients developed adenocarcinoma at the anal anastomosis.No dysplastic changes were detected during the first decade after surgery. Routine follow up of patients with chronic pouchitis with a hand-sewn anastomosis may not be necessary, although a small risk of cancer seems to remain at the anal anastomosis. The follow up should be focused on at-risk groups.

The malignancy of phaeochromocytomas is difficult to predict. Traditionally, only a metastasized tumour is considered malignant. The aim of this study was to assess the histopathological and clinical features, as well as the proliferative activity, and to analyse p53 and p21 expression in 105 phaeochromocytomas.All malignant phaeochromocytomas (n = 8) showed at least one of the histologically suspicious features, i.e. over five mitoses/10 high-power fields, necrosis, capsular or vascular invasion. Malignant tumours were larger, but the age and gender of the patients were not significantly different. All benign (n = 33) and most of the borderline (18/21) adrenal phaeochromocytomas had less than 6% Ki67+ tumour cells, while most malignant tumours (6/7) expressed Ki67 in6% of the cells. p53+ immunohistochemistry was found in two malignant tumours, while p21 expression did not correlate with malignancy.These data suggest that the lack of histologically suspicious features, low proliferative activity, smaller size, and negative p53 immunostaining point to a benign diagnosis in phaeochromocytomas.

In recent years, numerous serum and cell/tissue-based markers have been described for colorectal cancer (CRC). The aim of this article was to provide guidelines for the routine clinical use of some of these markers. Lack of sensitivity and specificity preclude the use of any available serum markers such as carcinoembryonic antigen (CEA), CA 19-9, CA 242, CA 72-4, tissue polypeptide antigen (TPA) or tissue polypeptide-specific antigen (TPS) for the early detection of CRC. However, preoperative measurement of CEA is desirable as this may give independent prognostic information, help with surgical management and provide a baseline level for subsequent determinations. For patients with stage 2 (Dukes' B) and 3 (Dukes' C) disease who may be candidates for liver resection, CEA levels should be measured every 2-3 months for at least 3 years after diagnosis. For monitoring treatment of advanced disease, CEA should also be tested every 2-3 months. Insufficient evidence is presently available to recommend the routine use of other serum markers for monitoring purposes. Similarly, the new cell and tissue-based markers (e.g, ras, P53) cannot yet be recommended for routine clinical use.

This paper presents a complete way of creating event-continuous models for hybrid systems. The development of the event model is formalised as well as the results, the latter being done using Petri nets. The continuous model is constructed using bond graphs with variable causality, including a suitable representation of the switch elements. >

The ability of the ligninolytic fungus Trametes trogii to degrade in vitro different xenobiotics (PCBs, PAHs and dyes) was evaluated. Either 200 ppm of a PCB mixture (Aroclor 1150) or 160 ppm of an industrial PAH mixture (10% V/V of PAHs, principal components hexaethylbenzene, naphthalene, 1-methyl naphthalene, acenaphthylene, anthracene, fluorene and phenanthrene), were added to trophophasic and idiophasic cultures growing in a nitrogen limited mineral medium (glucose/asparagine) and in a complex medium (malt extract/glucose). Gas-liquid chromatography proved that within 7 to 12 d more than 90% of the organopollutants added were removed. The decrease in absorbance at 620 nm demonstrated that cultures of this fungus were able to transform 80% of the dye Anthraquinone-blue (added at a concentration of 50 ppm) in 1.5 h. Enzyme estimations indicated high activity of laccase (up to 0.55 U/mL), as well as lower production of manganese-peroxidase. Laccase activity, detected in all the conditions assayed, could be implicated in the degradation of these organopollutants. Considering the results obtained, T. trogii seems promising for detoxification.

CEA, CA 19-9, CA 242 and CA 72-4 are commonly used tumour markers for gastrointestinal malignancies. The advantage of the concomitant use of these markers is under debate.Serum concentrations of the markers were measured at the time of diagnosis in 161 patients with benign and 125 with malignant gastrointestinal diseases. Concomitant use of the markers was evaluated in a logistic regression model.CA 19-9, CA 242 or CA 72-4 showed similar sensitivity of 44% for gastric cancer, whereas CEA was elevated in 25% of the cases. In patients with colorectal cancer, CEA was most frequently elevated (54%), followed by CA 242 (46%), CA 19-9 (36%) and CA 72-4 (25%). High CA 19-9 and CA 242 serum levels were frequent in patients with cholangiocarcinoma (86% and 68%, respectively) and pancreatic cancer (80% and 63%, respectively). In the benign disease group, serum CA 19-9 was most frequently elevated, i.e. in 24%, 25% and 38% of patients with pancreatic, biliary and liver disorders, respectively. The overall accuracy of CEA, CA 19-9, CA 242 and CA 72-4 was 66%, 71%, 71% and 66%, respectively (p0.18). When combined in a logistic regression model, CA 72-4, CA 19-9 and CEA provided independent diagnostic information, whereas CA 242 contributed with independent diagnostic information only on excluding CA 19-9. The probability of cancer for each patient, calculated with the model, was applied as a diagnostic test and was compared with the single markers by ROC-curve analysis. The AUC value of the probability index was significantly higher than the values of the different tumour markers.An algorithm based on the combination of CEA, CA 19-9 and CA 72-4 improved the diagnostic accuracy in gastrointestinal tract malignancies compared with these markers alone.

Human chorionic gonadotropin (hCG) beta in serum is a promising tumour marker for gastrointestinal malignancies. Our aim was to investigate the expression of hCGbeta by immunohistochemistry in various gastrointestinal cancers and benign tissues.A monoclonal antibody (MAb) specific for free hCGbeta was used to stain 107 tissue samples from various gastrointestinal malignancies and 36 benign or normal tissue samples. The specificity of the staining was verified and the results compared with those obtained with a widely used commercial polyclonal antibody (PAb) which reacts with both free hCGbeta and intact hCG, as well as with luteinizing hormone beta. With the MAb, we observed positive immunohistochemical staining in 24% of the malignant gastrointestinal tumours. Gastric (60%) and pancreatic (56%) carcinomas, as well as extrahepatic cholangiocarcinomas (36%), were positive most frequently. We also discovered immunoreactivity in half of the non-malignant samples from pancreatic and biliary tissues. With the PAb, hCG immunoreactivity was evident more frequently in some cancers, but the staining was diffuse and occasionally polymorphonuclear leucocytes were strongly stained.This study shows that our MAbs specific for hCGbeta are well suited for immunohistochemistry. Our results confirm previous findings on gastrointestinal cancers and, furthermore, we demonstrate hCGbeta tissue expression in pancreatic adenocarcinoma. The results support reports on hCGbeta as a serum tumour marker for digestive tract diseases.

Malignancy of pheochromocytomas is difficult to estimate on the basis of histopathological features. Good prognostic markers are not available. In our search for new markers to differentiate malignant pheochromocytomas from benign ones we tested the value of inhibin/activin subunit expression. Inhibins are heterodimeric glycoproteins consisting of an alpha-subunit and either a betaA- or a betaB-subunit. Activins are composed of beta-subunits only. Immunohistochemically inhibin/activin betaB-subunit was strongly positive in the normal adrenal medulla, but the cortex was negative. A striking difference was found in inhibin/activin betaB expression between benign and malignant pheochromocytomas. The majority of benign adrenal tumors (27 of 30) showed strong or moderate immunoreactivity, whereas all seven malignant tumors were negative or only weakly positive for inhibin/activin betaB-subunit. The percentage of positively staining cells varied greatly in extraadrenal pheochromocytomas and in those benign tumors that showed over 5 mitoses/10 high power fields, necrosis, or capsular or vascular invasion, here called borderline tumors. Inhibin/activin betaB messenger ribonucleic acid was also found in pheochromocytomas. However, no significant differences in messenger ribonucleic acid levels were found in various types of tumors. Weak immunohistochemical positivity for inhibin/activin betaA-subunit was detected in the adrenal cortex, but the medulla and most of the pheochromocytomas were negative. Our data show that inhibin/activin betaB-subunit is expressed in normal adrenal medullary cells. Strong staining is found in most benign adrenal pheochromocytomas, whereas malignant tumors are almost negative. This suggests that loss of inhibin/activin betaB-subunit expression in pheochromocytomas may be used as an indicator of malignant potential.

Syndecan-1, a cell surface heparan sulphate proteoglycan, has a role in cell adhesion, maturation and proliferation. Syndecan-1 has been reported to be a promising prognostic marker in various cancer forms.We analysed tumour specimens from 296 gastric cancer patients. Syndecan-1 expression was studied by immunohistochemistry.Syndecan-1 immunoreactivity was observed in 234 (79%) patients. The expression of syndecan-1 did not correlate significantly with the presence of lymph node metastases, distant metastases, peritoneal spreading, penetration depth, tumour size, tumour location, Borrmann's classification, Laurén's classification, age or gender. Syndecan-1 immunoreactivity correlated significantly with survival in the whole patient series (p = 0.0499) and also in the subgroup of patients with stage I cancer (p = 0.0417), but not in patients with stage II, III or IV disease. In multivariate survival analysis, stage of disease and tumour size emerged as the only independent prognostic factors.In conclusion, immunohistochemical expression of syndecan-1 is a potential prognostic factor in gastric cancer, especially in patients with stage I disease.

Production of the glycoprotein hormone hCG beta has been associated with aggressive behavior in nontrophoblastic tumors. In this study the prognostic value of serum level and tissue expression of hCG beta were compared in 232 patients with colorectal cancer.Serum levels were measured with a hCG beta specific immunofluorometric assay. Tissue specimens were stained with the same monoclonal antibody as in the serum assay.The proportion of patients with a positive immunohistochemical expression of hCG beta was higher (22%) than the proportion with elevated serum levels (17%). The correlation between serum and tissue expression was moderate (kappa 0.298). Both serum and tissue expression of hCG beta were independent prognostic factors. hCG beta serum level was a stronger prognostic factor than tissue expression both in uni- and in multivariate analysis. The accuracy when predicting 5-year survival status of the patients was highest (63%) when using the combined results of serum and tissue expression.There is a moderate correlation between hCG beta expression in serum and in tissue. The predictive accuracy of serum hCG beta was higher than the predictive accuracy of tissue expression, and the prognostic accuracy was further slightly increased when using a combination of tissue and serum expression.

As an audit of patients undergoing laparoscopic cholecystectomy this study not only reports the short term results, but attempted to assess the long term effect of the operation on the symptom profiles of the patients.Three hundred unselected consecutive patients underwent elective laparoscopic cholecystectomy from January 1991 to July 1994. Short term outcome was analysed by reviewing patient files for operation details, postoperative morbidity, complications, and gallbladder histology. Long term (median 2 years) outcome was evaluated by a detailed postal questionnaire. Symptomatic benefit ratios (BR) accruing from the laparoscopic removal of the gallbladder were calculated.Twelve operations (4.0%) were converted to open surgery and were excluded from long term outcome analyses. Median operation time was 93 (range 40-245) minutes. There were no deaths. Overall morbidity was 13 %. Median postoperative hospital stay was 2 days (range 1-18 days) and median time-off work 15 days (range 2-49 days). The overall response rate to the questionnaire was 87%. Only one of the 261 patients (0.4%) suffered from recurrent common bile duct stones so far. As shown by the benefit ratios the symptoms most effectively relieved by laparoscopic cholecystectomy were biliary pain (0.97), nausea (0.95), vomiting (0.96) and jaundice (0.94). Most patients with diarrhoea (0.70) and heartburn (0.66) felt relief. Constipation (0.39) and food intolerance (0.57) were unaffected. Most patients (90%) felt that the operation-initiating symptom had disappeared and 98 percent of the patients considered that they had obtained overall symptomatic improvement by the operation.Laparoscopic cholecystectomy appears to be a safe and effective way of treating the most common symptoms related to gallstone disease.

Increased serum concentrations of trypsin immunoreactivity occur in patients with biliary tract cancer. To characterize this trypsin, we developed a sensitive time-resolved immunofluorometric assay for trypsin-1 complexed with alpha(1)-antitrypsin (AAT) and studied the concentrations of this complex in sera from healthy individuals (n = 130) and patients with benign biliary disease (n = 32), biliary tract cancer (n = 17), pancreatic cancer (n = 27), and hepatocellular cancer (n = 12).We used a trypsin-1-specific monoclonal antibody on the solid phase and a europium-labeled polyclonal antibody to AAT as tracer. The detection limit was 0.42 microgram/L. The validity of the trypsin-1-AAT test for detection of biliary tract cancer was compared with trypsin-2-AAT and CA19-9.Increased concentrations of trypsin-1-AAT (33 microgram/L) were found in 76% of patients with biliary tract cancer, and the concentrations were significantly higher than in those with benign biliary disease (P0. 0001). The median concentration of trypsin-1-AAT in serum from patients with biliary tract cancer was 3.7-fold higher than in healthy controls, 2.6-fold higher than in patients with benign biliary tract disease, 1.7-fold higher than in patients with pancreatic cancer, and 2.0-fold higher than in patients with hepatocellular cancer.Of the markers studied, trypsin-1-AAT had the largest area (0.83) under the receiver operating curve in differentiating biliary tract cancer from benign biliary tract disease. Our results suggest that trypsin-1-AAT is a new potential marker for biliary tract cancer.

This study was conducted to evaluate the clinical usefulness of serum hCGbeta in the diagnosis and prognosis of patients (n = 59) with cancers of the oral cavity and oropharynx. As a reference marker we used squamous-cell carcinoma antigen (SCCAg). A blood sample was obtained from all patients before primary surgery. Serum hCGbeta was determined by a time-resolved immunofluorometric assay (IFMA) and SCCAg by a solid phase immunoenzymometric assay. Elevated preoperative hCGbeta levels were observed in 8 (14%) and elevated SCCAg in 12 (20%) out of 59 patients. Patients with preoperatively elevated hCGbeta had a shorter recurrence-free survival when compared with those with normal hCGbeta levels (log-rank Chi-squared = 6.83, p =.009), and the risk-ratio for recurrence during follow-up for those was 3.6 (95% CI = 1.29-9.94). In a Cox multivariate model hCGbeta (p = 0.039) and stage (p = 0.044) were independent prognostic factors. SCCAg showed no correlation with recurrence-free survival. We conclude that determination of hCGbeta in serum is a potential marker in the prognostic evaluation of patients with SCC of the oral cavity and oropharynx.

Laparoscopic adrenalectomy has become a viable option for removal of small adrenal neoplasms. We present our initial experience of this operation for primary aldosteronism. In this prospective study, 12 consecutive patients with primary aldosteronism were operated on laparoscopically by one surgeon. Operative time, blood loss, postoperative pain, complications, hospital stay, convalescence time, and outcome were analyzed. Five right-sided and seven left-sided adrenalectomies were performed in six female and six male patients with a mean age of 51 years. The mean operative time was 126 minutes. All procedures were successfully carried out laparoscopically. No major complications occurred. All patients turned normokalemic and the medication for hypertension could be stopped or diminished in all cases. The mean hospital stay was 3.4 days, and the mean sick leave was 13 days. Laparoscopic adrenalectomy seems to be a safe and effective treatment for primary aldosteronism and should be considered the operation of choice.

In the intact stomach, Helicobacter pylori associated gastritis is considered to be a risk factor for cancer. After partial gastrectomy increased mucosal cell proliferation associated with chronic bile reflux has been claimed to increase the risk for cancer in the gastric stump, whereas the influence of H. pylori infection is not so clear.The study was a retrospective study with 130 patients, who had undergone partial gastrectomy for peptic ulcer. The cell proliferation rate was determined from immunohistochemical stainings of gastroscopy biopsies with Ki-67 antibodies from gastric remnants.The mean labelling index (LI) was 30.8%. There was no clear association between H. pylori infection and proliferation rate. A significant difference in proliferation rate was seen between patients with a reconstruction type known to be associated with bile reflux and those with a reconstruction without bile reflux. The difference was small in H. pylori negative patients but strong in those with bile reflux and H. pylori infection. The LI increased with age. Smoking had no significant effect on proliferation whereas use of NSAIDs seemed to inhibit proliferation.Ki-67 is a convenient method for assessing the proliferation rate of the gastric epithelium. Bile reflux and H. pylori infection seem to have a synergistic effect on cell proliferation in the gastric remnant and may explain the increased risk of cancer after partial gastrectomy.

The prognostic value of the immunohistochemical expression of Ki-67 in paraffin embedded specimens was studied in 242 patients with gastric adenocarcinoma. The results were compared with ploidy and S-phase fraction (SPF) obtained by DNA flow cytometry. Both SPF and ploidy correlated with survival in univariate analysis. In multivariate survival analysis, stage of disease, DNA ploidy and presence of distant metastases emerged as independent prognostic parameters. There was no significant difference in survival between patients having tumours with high and low Ki-67 labelling, neither in univariatenor in multivariate survival analysis.

Serum concentrations of trypsinogen-2 and trypsin-2-alpha(1)-antitrypsin (trypsin-2-AAT) were determined in 145 patients with malignant and 61 with benign digestive-tract diseases. The validity of these tests for detection of cancer was compared with that of CA 19-9 and CEA. Elevated levels of trypsinogen-2 (90 micrograms/l) and trypsin-2-AAT (25 micrograms/l) were found in 46% and 42%, respectively, of patients with malignant disease and the levels of trypsinogen-2 were significantly higher than in those with benign disease (p0.005). High trypsinogen-2 and trypsin-2-AAT concentrations were found most often in patients with biliary and pancreatic cancer, but also in benign obstructive biliary disease. Our results suggest that trypsinogen-2 and trypsin-2-AAT are new potential markers for cholangiocarcinomas.

The prognostic value of the immunohistochemical expression of Sialyl Tn antigen (STn) was evaluated in 242 patients with gastric carcinoma. Formalin-fixed, paraffin-embedded specimens of gastric adenocarcinomas were stained with the monoclonal antibody C1282, produced by immunization with ovine submaxillary mucin (OSM). Positive immunoreactivity for STn was observed in 149 (62%) patients. The expression of STn did not correlate with stage of disease (TNM), tumour location, presence of lymph-node or distant metastases, histological type, age or gender. STn immunoreactivity correlated strongly with overall survival in univariate analysis. The median survival in the STn-positive group was 21 months, in comparison to 38 months in the STn-negative group. The difference in survival between STn-negative and STn-positive tumours was significant in patients with stage-I cancer, but not in patients with stage-II -III or -IV disease. STn immunoreactivity emerged as an independent prognostic factor in Cox multivariate analysis. It is concluded that the immunohistochemical expression of STn is a good marker in the prediction of survival in patients with stage-I gastric carcinoma.

Between January 1992 and December 1994, 5,742 patients were treated by laparoscopic cholecystectomy in 35 Finnish hospitals. The operation was converted to open laparotomy in 360 (6.3%) patients, the most common causes for conversion being technical difficulties in dissection of the gall bladder (2.8%), bleeding (0.9%) and bile duct injury (0.48%). Intraoperative cholangiography was performed selectively in 18%, and common bile duct stones were found in 10.2% of these cases. Postoperative complications occurred in 208 (3.6%) patients, of whom 65 (1.1%) required reoperation. Twenty-eight (0.48%) of these patients had common bile duct injury. In eighteen patients bilio-digestive Roux-en-Y reconstruction was performed, whereas 10 cases could be handled by endoscopic drainage or suturing and T-tube drainage. Thus, the total number of patients with bile duct injury was 56 (0.96%). The reported hospital mortality was 0.08%. The mean hospital stay and the mean sick leave were three days (range 1-41) and 13 days (range 1-60), respectively. These data demonstrate that laparoscopic cholecystectomy can be performed with acceptable morbidity and mortality rates as a routine method in various different hospitals.

The prognostic value of the novel tumour marker CA 242 was studied in 175 patients with pancreatic cancer and the results were compared with those of CA 19-9. Preoperative serum levels of CA 242 and CA 19-9 were determined by commercially available assays. Patients were classified according to UICC TNM-stage, and divided into three groups of resectable, non-resectable and advanced disease. The lowest cut-off levels that divided patients into groups with significant difference in survival were calculated. Patients with resectable disease and preoperative CA 242 below 25 U/ml had a significantly better prognosis than those with a higher level (p0.05). The corresponding cut-off values were 100 U/ml in non-resectable (p0.05) and 3500 U/ml in advanced disease (p0.05). It is noteworthy that the overall survival rate of patients who underwent resection for cure, but had a high preoperative CA 242 level, approached that of patients with non-resectable disease. In multivariate analysis, only resectability (p0.0001) and preoperative serum CA 242 level (p = 0.01) were independent prognostic factors. If TNM-stage was used instead of resectability, the results were similar (stage p0.0001, CA 242 p = 0.006). When CA 242 was excluded from the model, preoperative serum CA 19-9 level approached the borderline of significance as an independent prognostic factor (p = 0.07). In conclusion, the preoperative serum level of the novel tumour marker CA 242 is an independent prognostic factor in pancreatic cancer. CA 242 yielded more prognostic information than CA 19-9.

A key feasibility issue for the ITER Vanadium/Lithium breeding blanket is the question of insulator coatings. Design calculations show that an electrically insulating layer is necessary to maintain an acceptably low MHD pressure drop. To enable experimental investigations of the MHD performance of candidate insulator materials and the technology for putting them in place, the room-temperature ALEX (Argonne`s Liquid Metal EXperiment) NaK facility was upgraded to a 300{degrees}C lithium system. The objective of this upgrade was to modify the existing facility to the minimum extent necessary, consistent with providing a safe, flexible, and easy to operate MHD test facility which uses lithium at ITER-relevant temperatures, Hartmann numbers, and interaction parameters. The facility was designed to produce MHD pressure drop data, test section voltage distributions, and heat transfer data for mid-scale test sections and blanket mockups. The system design description for this lithium upgrade of the ALEX facility is given in this document.

A very large mesenteric desmoid tumour was found in a 19-year-old man. The tumour could be excised with free margins and no further therapy was given. One year after the operation the patient does well without any signs of recurrence.

Preclinical testing is an important part of cancer drug development. The aim of this thesis was to establish and evaluate preclinical in vitro methods useful in the development of new anticancer drugs. In paper I, the development of non-clonogenic assays (FMCA-GM) using CD34+ stem cells for assessment of haematological toxicity was described. A high correlation was seen when comparing the 50% inhibitory concentrations (IC50) from FMCA-GM with the IC50 from the established clonogenic assay (CFU-GM). In paper II, FMCA-GM was complemented with additional cell models, establishing a normal cell panel. In vitro toxicity towards the five normal cell types was compared with known clinical adverse event profiles. The normal cell panel roughly reflected the tissue specific toxicities but was most useful in the prediction of therapeutic index. In paper III the use of peripheral blood lymphocytes from human, dog, rat and mouse to detect species differences in cellular drug sensitivity was described. Good agreement between our method and the established CFU-GM assay was observed. In paper II the benefit of using primary tumour cells from patients to predict cancer diagnosis-specific activity was studied. The in vitro activity of fourteen anticancer drugs was tested in tumour samples of both haematological and solid tumour origin. In general, clinical activity was well reflected. In paper IV, the efficacy and toxicity models were applied for experimental follow-up of a novel inhibitor of the ubiquitin-proteasome system, CB3 (Phosphoric acid, 2,3-dihydro-1,1-dioxido-3-thienyl diphenyl ester). In the preliminary characterization of CB3, antitumour activity and a favourable toxicity profile were displayed, although the exact mechanism of action remains to be elucidated. CB3 will therefore be further investigated. In conclusion, the work presented here contributes to different parts of the preclinical drug development and the methods may aid in the characterization of anticancer compounds

Sensitive, specific time-resolved immunofluorometric assays were used to measure the concentrations of human choriogonadotropin (hCG), free beta-subunit (beta-hCG), and the core fragment of beta-hCG (c beta-hCG) in serum and urine of men and nonpregnant women without evidence of cancer. Concentrations of hCG and beta-hCG were measurable in 59-70% of serum samples and in 50-59% of urine samples. c beta-hCG was mostly undetectable in serum but measurable in 81% of urine samples. Concentrations were higher in women than in men, and hCG concentrations increased with age. Therefore, reference ranges based on the 97.5 percentile were calculated separately for women and men and for those50 and50 years. However, concentrations of hCG correlated much more strongly with those of follicle-stimulating hormone than with age. hCG concentrations in serum were similar to those reported before, but beta-hCG concentrations were below the detection limit of earlier assays, and the upper reference limit was one-fifth to one-tenth the cutoff concentrations used earlier. In urine, hCG and c beta-hCG were the major forms of hCG, and their concentrations were similar to those of hCG in serum.

One prominent strategy health-care institutions are pursuing today is the formation of regional networks providing comprehensive continuums of care. Regional activities can be organized according to several distinct geographical parameters: city, county, state, or multistate regions. Although the different types of regionalization may be beneficial, they will generate different types of activities and benefits. Another consideration is that regional structures can range from very loose affiliations to complete ownership. In 1987 the Sisters of Providence health system, Seattle, initiated efforts to create a functionally integrated regional healthcare system in the Portland, OR, market, which had a good framework in place for developing a vertically and horizontally linked comprehensive continuum of care. The Oregon Management Committee, composed of local administrators, was established to identify issues and develop common objectives. The group developed a regional strategic plan and identified eight key areas to begin regionally coordinated activities. It began creating working relationships among institutional counterparts and program integration in several outpatient service areas where duplication was evident. Another effort involved greater coordination of marketing activities.

Patients with pancreatic cancer usually lack signs and symptoms in the early course of the disease. Even when malignancy is suspected, differential diagnosis between benign and malignant pancreatic disorders may be difficult with current methods. An increasing interest has been focused on the utility of immunological tumour markers. CEA has been widely used since the early seventies, but the results in diagnosis of pancreatic cancer have been disappointing. Tumour marker tests for CA 19-9 and CA 50 are based on monoclonal antibodies to colonic carcinoma cell lines. CA 19-9 and CA 50 are strongly expressed in most tissue specimens from pancreatic carcinomas, but are also found in normal pancreas and benign pancreatic diseases. The CA 19-9 and CA 50 antigens are shed or released into the circulation, and are found in increased concentrations in 70-80% of patients with pancreatic cancer. Also 50-65% of patients with small resectable carcinomas have elevated CA 19-9 and CA 50 levels, although very high serum concentrations usually indicate advanced disease. Slightly elevated serum CA 19-9 and CA 50 levels are seen in some patients with benign pancreatic diseases, more often in acute than in chronic pancreatitis. Elevated values are often observed in patients with benign obstruction of the common bile duct, particularly in patients with cholangitis. In patients with jaundice of hepatocellular origin, the CA 19-9 and CA 50 levels are lower than in extrahepatic cholestasis. CA 19-9 and CA 50 have better diagnostic accuracy for pancreatic cancer than CEA, CA 125, DU-PAN-2, TPA and PSTI/TATI. However, the sensitivities and specificities of CA 19-9 and CA 50 are too low for screening of an asymptomatic population. Nevertheless, CA 19-9 and CA 50 have in our experience shown to be useful complements to other diagnostic methods in symptomatic patients with suspicion of pancreatic cancer. Combinations of different markers improve the sensitivity only slightly compared to the use of CA 19-9 or CA 50 alone. Follow-up using CA 19-9 and CA 50 is a simple and sensitive way of monitoring the postoperative course of patients with pancreatic cancer, and may give a lead time of several months for a recurrence compared to conventional methods.

We still lack clinically useful tumour markers in gastric cancer. To be of clinical value markers should be elevated in the early stages of the disease, when surgery for cure is possible. However, tumour markers available today, like CEA, CA 19-9 and CA 50, mainly detect advanced gastric cancer, for which only palliative treatment is available. The use of tumour markers in the follow-up of radically operated patients seems to be of only academic interest, mainly because a recurrence of gastric cancer is incurable. The preoperative tumour marker level may have a prognostic value and may be clinically useful in selecting patients for adjuvant treatment. To elucidate this, prospective controlled trials are needed. A short review of tumour markers in gastric cancer will be presented.