Metabolic effects of propofol in the isolated perfused rat liver

Inhibitory effects of the intravenous anaesthetic propofol on mitochondrial energy metabolism have been reported by several authors. Impairment of energy metabolism is usually coupled to reduction in ATP production, which in turn is expected to lead to several alterations in cell metabolism such as stimulation of glycolysis and inhibition of gluconeogenesis. The present work aimed at finding an answer to the question of how propofol affects energy metabolism-linked parameters in the isolated perfused rat liver. In the fed state, propofol increased glycogenolysis (glucose release), glycolysis (lactate and pyruvate production) and oxygen uptake in the range between 10 and 500 microM. In the liver of fasted rats, propofol up to 100 microM increased oxygen uptake but decreased gluconeogenesis from three different substrates: lactate, alanine and glycerol. When lactate was the substrate 50% inhibition occurred at a propofol concentration of 50 microM. Propofol (100 microM) decreased the ATP content of the liver (-33.3%), increased the AMP content (+25%) and decreased the ATP/ADP and ATP/AMP ratios (49 and 45%, respectively). Most effects of propofol are probably due to impairment of oxidative phosphorylation. Particularly, the combined differential action on oxygen uptake (stimulation) and gluconeogenesis (inhibition) is strongly suggestive of an uncoupling action also under the conditions of the intact cell. This effect, in turn, is consistent with the reported high affinity of the cellular hepatic structure, especially membranes, for propofol.     

Multidrug-resistant cancer cells facilitate E1-independent adenoviral replication: impact for cancer gene therapy

Resistance to chemotherapy is responsible for a failure of current treatment regimens in cancer patients. We have reported previously that the Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug resistant-tumor phenotype. YB-1 predicts drug resistance and patient outcome in breast cancer. Thus, YB-1 is a promising target for new therapeutic approaches to defeat multidrug resistance. In drug-resistant cancer cells and in adenovirus-infected cells YB-1 is found in the nucleus. Nuclear accumulation of YB-1 in adenovirus-infected cells is a function of the E1 region, and we have shown that YB-1 facilitates adenovirus replication. Here we report that E1A-deleted or mutant adenovirus vectors, such as Ad312 and Ad520, replicate efficiently in multidrug-resistant (MDR) cancer cells and induce an adenovirus cytopathic effect resulting in host cell lysis. Thus, replication-defective adenoviruses are a previously unrecognized vector system for a selective elimination of MDR cancer cells. Our work forms the basis for the development of novel oncolytic adenovirus vectors for the treatment of MDR malignant diseases in the clinical setting.     

Assessment of highly angiogenic and disseminated in the peripheral blood disease in breast cancer patients predicts for resistance to adjuvant chemotherapy and early relapse

The assessment of tumor molecular features in combination with the detection of occult malignant cells may provide important clinical information, beyond the standard staging of breast cancer. Using a nested RT-PCR technique, we assessed prospectively the presence of cytokeratin-19 (CK19) mRNA positive cells in the blood of 100 operated patients with breast cancer before the initiation of adjuvant chemotherapy and local radiotherapy. Tissue samples were prospectively collected and analyzed for estrogen (ER) and progesterone (PgR) receptor, c-erbB-2 overexpression, mutant-p53 and bcl-2 protein accumulation, proliferation index and microvessel density (MVD). CK-19 mRNA-positive cells were detected in the peripheral blood of 33% of patients. Simultaneous display of high intratumoral MVD and of CK-19 mRNA-positive cells, which characterized highly angiogenic and disseminated in the peripheral blood (HAD) disease was noted in 25% of patients. Detection of CK-19 positive cells was significantly associated with increased MVD (p = 0.002). In univariate analysis (median follow-up 30 months) CK19 mRNA detection and MVD were the most significant factors related to a short relapse-free survival (RFS), (p < 0.0001). In multivariate analysis, CK19 positivity, high MVD and c-erbB-2 overexpression were the only significant and independent variables associated with relapse (p = 0.0005, 0.03 and 0.04, respectively). Patients with HAD had an expected relapse rate close to 70% vs. <5% in the remaining patients irrespectively of the used chemotherapy regimen. The simultaneous presence of high MVD and CK19-positive cells in the blood of patients with early breast is linked with poor prognosis, which cannot be improved with standard chemotherapy regimens.     

Increased serum CA-15.3 levels in patients with megaloblastic anemia due to vitamin B12 deficiency

OBJECTIVES: To estimate the usefulness of serum tumor markers' monitoring, as predictors of gastric cancer in patients with pernicious anemia. PATIENTS AND METHODS: We investigated serum levels of carcinoembryonic antigen (CEA), alpha-fetal protein, cancer antigen (CA)-19.9, CA-125 and CA-15.3 in 50 patients with pernicious anemia and in 24 healthy controls, matched for age and sex. In 38 patients, the evaluation was repeated 1-6 months after the correction of cobalamin deficiency. RESULTS: All patients and controls had normal serum CEA and alpha-FP, and the levels of these markers as well as those of CA-125 and CA-19.9 did not differ between the two groups. All 50 patients, but only 2 controls exhibited increased serum CA-15.3, and the difference between the two groups was very significant (129.4 +/- 84.9 vs. 19.8 +/- 7.3 IU/ml, p < 0.001), while no difference between males and females was found. A thorough clinical examination of all patients, and mammographic study in 18 females did not reveal any finding suspicious of breast cancer. CA-15.3 levels were positively correlated with serum lactate dehydrogenase, and negatively with B(12) and hemoglobin, but they were substantially decreased after the correction of anemia, in all 38 patients tested, and in 33 of them they were restored to normal. After a median follow-up of 34 months, one patient developed a colon cancer, but none showed any sign suspicious of breast cancer. CONCLUSIONS: Serum CA-15.3 shows an aberrant increase in untreated patients with pernicious anemia, which is reversed after the correction of the anemia. The possible origin seems unrelated to mammary tissue, and may be released by the apoptosing bone marrow megaloblastic erythroblasts.     

Evaluation of quality of life of patients with oral squamous cell carcinoma. Comparison of two treatment protocols in a prospective study

BACKGROUND AND PURPOSE: In recent years, various therapeutic concepts have been developed for treating oral cancer, these include preoperative simultaneous "neoadjuvant" radio-chemotherapy and one-stage-surgery with tumour ablation and reconstruction. When considering long-term survival, there is substantial evidence that the neoadjuvant therapy is superior to the primary surgical approach with postoperative radiation. Both treatment concepts, however, have a strong impact on the quality of life. PATIENTS AND METHODS: This study prospectively evaluates and compares quality of life in 53 patients with oral cancer treated according to a neoadjuvant concept or primarily surgically, using the questionnaires QLQ C-30 and H and N35 by the EORTC. RESULTS: Initially both groups showed a marked reduction in the quality of life. Despite a clear improvement in the first postoperative year baseline values were not reached in most of the scores. Specific long-lasting impairments in the symptom scales concerning oral functions were found in both treatment arms. In the neoadjuvant therapy group, however, especially global health and the emotional status were reduced to a higher degree than in the other group. This was particularly noticeable in the early treatment phase. CONCLUSIONS: Following an initial deterioration of quality-of-life after 3 months a gradual improvement of physical and psychological function was observed in the course of the first post-treatment year in both groups. Severe side effects can be observed. These side effects vary strongly in their individual expression. Limitations in the quality of life can be justified, if the more aggressive therapy resulted in a better disease free survival.     

The impact of stromal cell contamination on chemosensitivity testing of head and neck carcinoma

BACKGROUND: Reliable chemosensitivity testing of head and neck squamous cell carcinoma (HNSCC) still faces methodical limitations. Since stromal cell contamination has been found to preclude reliable radiosensitivity testing of HNSCC as well as chemosensitivity testing of lung tumors, the present study investigates the impact of stromal cell contamination on chemosensitivity testing of HNSCC. PATIENTS AND METHODS: Seventeen biopsies from HNSCC were analyzed. The specimens were investigated using an ex vivo colony formation assay which allows for the quantitative and separate determination of the overall, as well as the epithelial, and stromal response to carboplatin, 5-fluorouracil and docetaxel. RESULTS: The overall chemoresponse was dominated by stromal cell multidrug resistance. However, by selective evaluation of the epithelial chemoresponse, individual chemosensitivity patterns could be identified. CONCLUSION: Multidrug-resistant stromal cells preclude the reliable assessment of the chemoresponse of HNSCC specimens. Carefiul correction for stromal cell effects is a prerequisite for the generation of therapeutically useful information.     

Alcohol and ovarian cancer risk: results from the Netherlands Cohort Study

OBJECTIVE: To study alcohol consumption in relation to ovarian cancer risk in a prospective cohort study. METHODS: The Netherlands Cohort Study on diet and cancer was initiated in 1986. A self-administered questionnaire on dietary habits and other risk factors for cancer was completed by 62,573 postmenopausal women. Follow-up for cancer was established by annual record linkages with the Netherlands Cancer Registry. After 9.3 years of follow-up, 214 incident invasive epithelial ovarian cancer cases and 2211 subcohort members with complete data on alcohol intake were available for analysis. All incidence rate ratios (RRs) were corrected for age, use of oral contraceptives, parity, height, body mass index, energy intake and current cigarette smoking. RESULTS: The RRs of ovarian cancer for women who consumed up to 5, 15 and >15 g of alcohol per day were 1.13 (95% confidence interval, 95% CI = 0.79-1.63), 0.85 (95% CI = 0.53-1.37) and 0.92 (95% CI = 0.55-1.54), respectively, compared to non-drinkers. Alcohol consumption in the form of wine, beer or liquor was not associated with ovarian cancer risk. CONCLUSION: These data do not suggest a major association between alcohol intake and ovarian cancer risk in this population.     

Tobacco and Alcohol Consumption and the Risk of Non-Hodgkin Lymphoma

OBJECTIVE: The aim was to test whether non-Hodgkin lymphoma (NHL) is associated with smoking or alcohol. METHODS: A case-control study recruited NHL cases aged 18-64 in parts of England between 1998 and 2001. One control was matched to each case on sex, date of birth and area of residence. Self-reported histories of tobacco and alcohol consumption were collected during face-to-face interviews. RESULTS: Among 700 cases and 915 controls, no association of smoking with the risk of NHL was observed [odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.85-1.28]. Risks were not raised with age started smoking, number of years smoked, and number of years stopped smoking. Compared with persons who drank alcohol once or twice a week, neither abstainers (OR = 1.03, 95% CI: 0.64-1.67), nor consumers of alcohol one to five times a year (OR = 1.35, 95% CI: 0.95-1.93), one to two times a month (OR = 1.20, 95% CI: 0.87-1.65), three to four times a week (OR = 0.82, 95% CI: 0.62-1.10), or most days (OR = 0.94, 95% CI: 0.70-1.25) increased their risk of developing NHL. Average daily volume or high occasional alcohol consumption were not associated with NHL. CONCLUSIONS: NHL was not associated with smoking or alcohol, but collaborative studies could further investigate the risks of rarer WHO subtypes following these exposures.