Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer.

BACKGROUND: Pancreas cancer is a dreaded disease with high mortality, despite progress in surgical and oncological treatments in recent years. The field is hampered by a lack of good prognostic and predictive tumour biomarkers to be used during follow-up of patients. METHODS: The circulating level of type IV collagen was measured by ELISA in pancreas cancer patients and controls. The expression pattern of type IV collagen in normal pancreas, pancreas cancer tissue and in pancreas cancer cell lines was studied by immunofluorescence and Western blot techniques. RESULTS: Patients with pancreas cancer have significantly increased circulating levels of type IV collagen. In pancreas cancer tissue high levels of type IV collagen expression was found in close proximity to cancer cells in the tumour stroma. Furthermore, pancreas cancer cells were found to produce and secrete type IV collagen in vitro, which in part can explain the high type IV collagen expression observed in pancreas cancer tissue, and the increased circulating levels in pancreas cancer patients. Of clinical importance, our results show that the circulating level of type IV collagen after surgery is strongly related to prognosis in patients treated for pancreas cancer by pancreatico-duodenectomy with curative intent. Persisting high levels of circulating type IV collagen after surgery indicates a quick relapse in disease and poor survival. CONCLUSION: Our results most importantly show that stroma related substances can be evaluated as potential cancer biomarkers, and thereby underline the importance of the tumour microenvironment also in this context.

Phase I/II trial of intraperitoneal 5-Fluorouracil with and without intravenous vasopressin in non-resectable pancreas cancer.

BACKGROUND: Systemic palliative treatment with chemotherapy against advanced pancreas cancer has low effectiveness despite considerable toxicity. AIM: To investigate the safety, toxicity and tumour response of intraperitoneal 5-Fluorouracil (5-FU) with intravenous Leucovorin and to monitor 5-FU pharmacokinetics in plasma during intraperitoneal instillation with and without vasopressin in patients with non-resectable pancreas cancer. PATIENTS/METHODS: Between 1994 and 2003, 68 patients with non-resectable pancreas cancer TNM stage III and IV, were enrolled to receive intraperitoneal5-FU instillation 750-1500 mg/m2 and intravenous Leucovorin 100 mg/m2 for two days every third week. Tumour response, performance status and toxicity were recorded. Seventeen patients were also treated with intravenous vasopressin 0.1 IU/minute for 180 minutes, during intraperitoneal 5-FU instillation. Area under the curve (AUC) and peak concentration (Cmax) of 5-FU in plasma were analysed. RESULTS: The treatment was well tolerated with minor toxicity. One complete response (54.1+ months) and 2 partial responses were observed. Time to progression was 4.4 months (0.8-54.1+), and median survival was 8.0 months (0.8-54.1+). There was a significant reduction of 5-FU Cmax in plasma the second day of treatment if vasopressin was used (3.4+/-2.5 and 6.1+/-5.4 mumol/l, respectively, p<0.05). 5-FU AUC in plasma was not significantly affected by vasopressin either day of treatment. CONCLUSION: Intraperitoneal 5-FU is a safe treatment with low toxicity to patients with non-resectable pancreas cancer. Tumour response was 4.4% and median survival time 8.0 months. Addition of vasopressin did not significantly decrease plasma 5-FU AUC but reduced Cmax on day 2 of treatment.

133Xe clearance estimates the effect of vasopressin on peritoneal blood flow in rats.

BACKGROUND/AIMS: When assessing the peritoneal microcirculation with invasive methods, interference with the mechanisms of vaso-regulation may occur. The 133Xe clearance technique renders the possibility, by minimal invasiveness, to estimate the influence of a vasoactive agent on the peritoneal microcirculation. METHODOLOGY: Ten to 15MBq of 133Xe were injected in the abdominal cavity in thirty-eight Wistar-FU (W-FU) rats and 35 Lister-Hooded (LH) rats. A NaI (Tl)-scintillation detector registered activity before and during vasopressin infusion. Gamma camera imaging confirmed the washout from the abdominal cavity. The laser Doppler flowmetry technique was used as a comparison. RESULTS: Vasopressin at 0.07 IU/kg/min IV significantly reduced 133Xe-clearance by 37% (p = 0.029) and 52% (p=0.036) and laser Doppler flowmetry by 69% (p=0.0019) and 44% (p=0.0039) in W-FU and LH rats, respectively. A linear correlation between dose of vasopressin and relative decrease in 133Xe clearance was demonstrated in the W-FU rat model (r2=0.98, p=0.023). The 133Xe clearance from the abdominal cavity in rat using a single-compartment model or the slow compartment in a double-compartment model gave reproducible information. CONCLUSIONS: The usefulness of this mini-invasive technique for sequential measurements before and during intervention will render the 133Xe clearance suitable for assessment of blood flow changes in the abdominal cavity.

Effect of carcinomatosis and intraperitoneal 5-fluorouracil on peritoneal blood flow modulated by vasopressin in the rat as measured with the 133Xe-clearance technique.

PURPOSE: Intraperitoneal administration of 5-fluorouracil for the treatment of gastrointestinal malignancies results in a greater total drug exposure in the peritoneal fluid than in plasma. Drugs are eliminated from the peritoneal cavity mainly by capillaries leading to the portal venous system and to a lesser extent by lymphatics. The drug itself and the presence of peritoneal carcinomatosis may affect elimination of the drug. The 133Xe-clearance technique allows the influence of a vasoactive agent on the peritoneal blood flow to be estimated with minimal invasiveness. The aim of the present study was to explore whether intraperitoneal 5-FU or peritoneal carcinomatosis affects the peritoneal blood flow and its reactivity to intravenous vasopressin, as measured indirectly with the 133Xe-clearance technique. METHODS: The animals used in this study were 63 Wistar-Fu (W-Fu) rats and 67 Lister-Hooded (LH) rats. On day 0, either 5-FU at 25 mg/kg body weight in 25 ml/kg isotonic saline was instilled intraperitoneally, or 1 x 10(5) syngeneic tumour cells were inoculated intraperitoneally. On days 1, 2 and 3 in the 5-FU-treated rats, and on days 12-16 in rats inoculated with tumour cells, peritoneal blood flow was analysed with the 133Xe-clearance technique, before and during intravenous infusion of vasopressin at 0.07 IU/min/kg body weight. RESULTS: The basal 133Xe-clearance before administration of vasopressin was similar in all groups except in the LH rats treated with 5-FU in which it was significantly lower. Infusion of vasopressin induced a significant decrease in 133Xe-clearance of the same magnitude in controls and in tumour-bearing rats. In the rats given intraperitoneal 5-FU, vasopressin did not reduce the 133Xe-clearance the first day after administration of 5-FU. CONCLUSIONS: Intravenous vasopressin at 0.07 IU/min/kg decreased peritoneal blood flow as measured indirectly with the 133Xe-clearance method. Intraperitoneal 5-FU abrogated the reduction in peritoneal blood flow with intravenous vasopressin the first day after treatment. In contrast, the presence of peritoneal carcinomatosis did not influence peritoneal blood flow, nor the effect of vasopressin

Blood flow in liver tumors--effects of vasoactive drugs estimated with xenon (133Xe) clearance.

BACKGROUND/AIMS: The aim of the present study was to identify in a standardized experimental rat liver tumor system the drugs which are most appropriate in influencing the relationship between liver tumor and normal liver parenchyma blood flow as estimated with 133Xe washout clearance method, and thereby positively influencing the kinetics of chemotherapeutic drugs. A battery of vasoactive drugs, which according to a literature review were considered to be active, were tested. METHODOLOGY: Twelve drugs were administered intravenously on 113 Wistar-Fu rats with an experimental adenocarcinoma in the liver (weight 0.62 g). 133Xe was applied in the tumor and in normal parenchyma with and without administration of a vasoactive drug. The pulses were registered with a NaI (Tl)-scintillation detector connected to a multichannel analyzer. The disappearance rate of the isotope was calculated according to a single compartment model. Four recordings were performed in each rat randomly in tumor and liver parenchyma with and without a drug (series A) and one series twice in tumor and twice in parenchyma with a drug (series B). RESULTS: In unaffected animals the tumor to liver quotient was 0.57+/-0.35. This quotient was higher in tumors less than 0.53 g. Angiotensin-II 8 mg i.v. increased the quotient to 0.95+/-0.20. No other drug significantly influenced the quotient. CONCLUSIONS: In an experimental adenocarcinoma in the liver this study has investigated the possibility of increasing the tumor to normal liver parenchyma blood flow quotient by a variety of vasoactive substances for the beneficial modification of tumor blood flow. Angiotensin II 8 mg i.v. was the only drug, which increased the quotient. None of the other tested drugs were supporting previous presented results on influencing tumor blood flow.

A comparison between hepatic artery ligation and portal 5-Fu infusion versus 5-Fu intra arterial infusion for colorectal liver metastases.

AIM: A prospective randomized study was executed comparing two regimens of regional therapy for liver metastases from colorectal cancer. METHODS: Eighteen patients were allocated to hepatic artery occlusion for 16 h followed by intraportal 5-fluorouracil (5-Fu) infusion (1000 mg/m(2)) for 5 days every sixth week (HAO). Twenty-one patients received intra-arterial 5-Fu infusion+Leucovorin (100 mg) i.v. for 2 days every second week (HAI). The follow up every third month included CT and CEA. Thirteen patients had limited extrahepatic cancer. At tumor progression regional therapy was stopped and systemic chemotherapy or the best supportive care was administered. RESULTS: The study was discontinued after randomization of 39 patients. No significant difference in survival within patients with and without extrahepatic cancer was present. The mean survival was longer in the HAI group than for the HAO group (19 months versus 13 months, p=0.0147) (median 18 (8-37) versus 12 (2-26). PR and SD were registered in 8/18 in the HAO group and 17/21 patients in HAI group. The median time to progress was 4 (1-22) months versus 7 (1-23) months for the HAO and HAI group, respectively. CONCLUSION: Regional intraarterial infusion with 5-Fu gives significantly better survival than hepatic artery occlusion followed by portal infusion. A limited amount of extrahepatic cancer does not influence survival time. A trial comparing hepatic artery 5-FU infusion and Leucovorin versus the most effective systemic therapy is warranted.

Treatment of non-resectable pancreatic cancer with intraperitoneal 5-FU and leucovorin IV.

AIM: To explore the feasibility of intraperitoneal (IP) 5-fluorouracil (5-FU) and (IV) leucovorin for patients with advanced pancreatic carcinoma. MATERIALS AND METHOD: Thirty patients (11 men), median age 65 (range 36-74 years), with a non-resectable pancreatic carcinoma in stage III (n=2) and IV (n=28) were treated with IP 5-FU 750-1000 mg/m(2)and leucovorin IV 100 mg/m(2)for 2 days every 3rd week. Tumour effect was analysed with repeated computed tomography (CT) scans, performance status was estimated with Karnofsky's index (KI) and morphine consumption, and toxicity assessed using World Health Organization (WHO) criteria. RESULTS: Median survival time was 7 months (range 0-21). There was no difference in survival between patients with different grading, staging or tumour size. Regional and systemic toxicity: The treatment was well tolerated, with no grade III or IV complications or side-effects. The median KI showed a minor reduction during treatment. The median morphine consumption per 24 hours increased from 0 mg (range 0-250) at inclusion, to 70 mg (range 0-540) at exclusion. The median nadir (WBC) was 7.2x10(3)/mm(3)(range 5.2-18.8). All patients had abdominal discomfort and distension during IP installation. CONCLUSION: Intraperitoneal administration of 5-FU is feasible for patients with nonresectable pancreatic carcinoma. The treatment can induce a temporary stabilization of tumour growth and eventually prolong survival without adverse effects.

Fast, robust total variation-based reconstruction of noisy, blurred images.

Tikhonov regularization with a modified total variation regularization functional is used to recover an image from noisy, blurred data. This approach is appropriate for image processing in that it does not place a priori smoothness conditions on the solution image. An efficient algorithm is presented for the discretized problem that combines a fixed point iteration to handle nonlinearity with a new, effective preconditioned conjugate gradient iteration for large linear systems. Reconstructions, convergence results, and a direct comparison with a fast linear solver are presented for a satellite image reconstruction application.

Human leukocyte interferon alpha (HLI-alpha) for treatment of pleural effusion caused by non small cell lung cancer. A pilot study.

Fourteen patients with ipsilateral pleural effusion from non small cell cancer of the lung, 10 of them with generalized metastasis, were treated with local application of HLI-alpha in addition to other symptomatic treatment. Cytology of pleural fluid at the beginning of treatment yielded cancer cells in all but one. HLI-alpha, 2 x 10(6) International Units (I.U.) diluted in 20 ml of distilled water was injected intrapleurally each time. The mean survival of the HLI-alpha treated patients, measured from the first treatment of the pleural effusion, was 10.8 months. The performance status improved in 9 patients following HLI-alpha treatment. The pleural effusion eventually ceased accumulating in all patients. To judge from cytology of tapped pleural fluid, the cancer cells disappeared during treatment with HLI-alpha in 11 patients.

Overview: foundations of cultural psychiatry.

The authors demonstrate the significance of adding the cultural dimension to basic psychiatric concepts. They point out the areas in which the work of anthropology and social psychology are relevant to psychiatry, including understanding mental health and illness, child-rearing practices and their effects on personality, cognition, family and social networks, sex roles and behavior, alcohol use, communication, and therapy. They also present some of the major conceptual foundations of cultural psychiatry, which include ethnography, emic and etic approaches, the cross-cultural approach, and the study of subjective culture.