A subchronic 90-day oral rat toxicity study and in vitro genotoxicity studies with a conjugated linoleic acid product

Conjugated linoleic acid (CLA) is the term given to a group of positional and geometric isomers of the essential fatty acid linoleic acid. CLA is found naturally in foods such as dairy and meat products. CLA is reported to have a number of beneficial effects including anticarcinogenic activity. However, safety data are limited. Clarinol™ G80 is a commercial preparation containing equal amounts of the 9cis,11trans and 10trans,12cis CLA isomers in the form of glycerides. In order to support the safety-in-use of Clarinol™ G80 as an ingredient in food, the preparation was tested in two in vitro mutagenicity assays, an Ames test and an in vitro cytogenetics assay, and a 90-day repeat-dose oral toxicity rat study. Clarinol™ G80 was non-mutagenic in both in vitro assays. In the 90-day study, Clarinol™ G80 produced hepatocellular hypertrophy in female rats at the highest dose level (15% w/w). This effect was an adaptive effect in response to feeding high levels of Clarinol™ G80 in the diet and was reversible upon withdrawal of test material. An increase in plasma insulin levels was also observed female rats fed 15% w/w Clarinol™ G80 but there was no effect on plasma glucose levels. A No Observed Adverse Effect Level of 2433 mg/kg bw/day for male and 2728 mg/kg bw/day female rats was identified in the study.     

Positron emission tomography in combination with sentinel node biopsy reduces the rate of elective neck dissections in the treatment of oral and oropharyngeal cancer.

PURPOSE: To assess the impact of a diagnostic ladder including [(18)F]fluorodeoxyglucose positron emission tomography (PET) and lymphoscintigraphy guided sentinel node biopsy (LS/SNB) on neck treatment in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). PATIENTS AND METHODS: Prospectively, 62 patients with resectable T1-3 OOSCC underwent computed tomography (CT) and PET. Patients without neck uptake in PET were defined as cN0 and were accrued for LS/SNB. Results were correlated with histopathology. The traditional guidelines according to CT findings were compared to the actual regimen and the outcome. RESULTS: Sensitivity, specificity, validity, and positive and negative predictive value of PET versus CT were 72% v 89%, 82% v 77%, 79% v 80.5%, 62% v 61.5%, and 88% v 94.5% (not significant). Thirty-eight PET negative patients underwent LS/SNB. Sentinel lymph nodes were found in all 38 patients. Five patients had positive nodes (PET false-negatives) and underwent neck dissection (ND). Fifty-one neck sides in 36 patients who were CT-negative would have been treated with selective ND according to the guidelines, and at least 45 neck sides would have had to undergo extensive ND because of positive CT findings (96 of 124 neck sides). In contrast, PET in combination with LS/SNB spared 59 neck sides, and 41 of 124 neck sides actually underwent ND as a result of PET staging, LS/SNB, and intraoperative decision. After a median follow-up of 35 months, two patients (both cN+ve and pN+ve) suffered from neck relapses. CONCLUSION: Diagnostics using PET in combination with LS/SNB considerably reduced the number of extensive ND in OOSCC as compared to CT without locoregional hazard.     

Lasting remission following multimodal treatment in a patient with metastatic breast cancer

We report on a lasting remission from multimodal treatment in a patient with hepatic metastasized breast cancer. After surgical removal of a singular hepatic metastasis, the patient underwent leukapheresis of peripheral blood mononuclear cell (PBMCs). For induction chemotherapy, the patient received 2 cycles of epirubicin and paclitaxel (ET). After 1 cycle of epirubicin and ifosfamide (EI), peripheral blood stem cells were harvested. After a final cycle of ET, the patient underwent high-dose chemotherapy (HDCT; thiotepa 600 mg/m/melphalan 180 mg/m) and autologous stem cell transplantation. Once reconstitution was achieved, PBMCs were reinfused followed by i.v. application of a trifunctional antibody (TrAb) with specificities anti-EpCAMxanti-CD3. TrAbs are able to simultaneously bind tumor cells, T cells, and additionally FcgammaR type I and III+accessory cells via their Fc region. Side-effects during treatment were hematotoxicity, mucositis and gastrointestinal toxicity. TrAb treatment resulted in intermittent fever, chills, elevated liver enzymes, systemic inflammatory response syndrome and pulmonary leakage. With a follow-up period of more than 8 years the patient is still in remission (96+months). This case suggests the feasibility and efficacy of combining surgery, standard and HDCT, and subsequent immunotherapy in metastatic breast cancer. Further investigation of this approach is indicated in a subgroup of patients with oligometastatic breast cancer.     

Differentiated thyroid carcinoma: the new UICC 6th edition TNM classification system in a retrospective analysis of 169 patients.

AIM: To compare the new, 6th edition, UICC TNM staging system with the former edition, we updated TNM staging in patients with differentiated thyroid carcinoma. METHODS: The new and old TNM classification systems for differentiated thyroid carcinoma were applied in a retrospective analysis of 169 patients who underwent therapy with radioiodine (131I) from 1975 through 2002 at the Department of Nuclear Medicine, Frankfurt. RESULTS: According to the new staging system, 83 patients (49%) were classified as T1 compared to 54 patients (32%) based on the former edition; 32 patients (19%) as T2 compared to 61 (36%) patients formerly. In 44 patients with minimal extrathyroid extension, formerly classified T4, the new TNM staging changed to T3, and no patient was classified T4. The one year relapse-free survival fraction under the former edition staging was 100% for T1 and 92.2% for T2, compared to 96.8% for new edition T1 and 93.3% for T2. CONCLUSION: The new TNM classification causes a significant change in staging. New T1 classified tumors had a slightly worse relapse-free survival fraction compared with the old T1 carcinomas. For patients treated at our department, the altered criteria for classifying extrathyroid extensions have had only a minor impact on disease management.     

Comparison of different methods to measure fibrinogen concentration in canine plasma with respect to their sensitivity towards the fibrinogen degradation products X, Y and D

In this study, fibrinogen measurements according to the Clauss method, photometric method and Jacobsson method have been investigated to find out how they are influenced by adding in vitro the purified canine fibrinogen degradation products (FDP) X, Y and D. Test results according to the Clauss method were found to be underestimated if the fragments X, Y and D were added while measurements according to the Jacobsson method turned out to underestimate the real fibrinogen concentration if the FDP Y and D were added. The Clauss method was particularly sensitive towards FDP. Results were considerably underestimated even with a quantity as little as 0.05 g FDP Y or FDP D/g fibrinogen (p < 0.05). The photometric method was only affected by FDP X leading to false high results. If FDP X was added, fibrinogen values were also overestimated with the Jacobsson method. Our results demonstrate that the photometric method is the most accurate.     

Type I nitric oxide synthase in the human lung is predominantly expressed in capillary endothelial cells.

Nitric oxide (NO) has important functions in the regulation of pulmonary smooth muscle tone. In the human lung, published data on the expression and distribution of neuronal nitric oxide synthase (NOS-I) are contradictory. The aim of this study, therefore, was to determine the predominant cells expressing NOS-I in the human lung. Immunofluorescence double staining techniques were applied to normal human lung tissue using established monospecific antibodies directed against NOS-I. Suprisingly, capillary endothelial cells in the alveolar septa were identified as the major sites of NOS-I expression. Neither alveolar nor bronchiolar epithelium, nor the alveolar macrophages, expressed NOS-I. These results indicate that the predominant sites of NOS-I expression in the human lung are confined to non-neuronal, i.e. capillary endothelial cells and suggest a role for NO in the regulation of pulmonary endothelial cell permeability.     

Endurance training modifies exercise-induced activation of blood coagulation: RCT

Randomized controlled trials (RCTs) on the topic of physical training and blood coagulation are rare and the effects are unclear. The aim of this study was to investigate whether endurance training adjusts blood coagulation and fibrinolysis at rest and after exercise. The study included 50 healthy untrained non-smokers randomized into training (TR 49 ± 6 years) or control group (CO 48 ± 6 years). Each subject performed an exercise test adjusted at 80 % individual anaerobic threshold (IAT) for 60 min before and after 12 weeks (80 % IAT: before TR 123 ± 20, CO 125 ± 26 W; after TR 148 ± 23 W, CO 127 ± 25 W; mean ± SD). Blood was taken at rest and after exercise to determine coagulation (e.g., aPTT, thrombin potential, TAT, F1+2, several coagulation factors) and fibrinolytic (e.g., tPA, PAI) parameters. The training intervention induced an elevation of physical capacity in TR by 17 % (rel. VO_2max) that led to a statistical relevant prolongation of aPTT at rest. Although absolute power output during the second exercise test was 20 % higher in TR, we detected an attenuated exercise-induced decrease of aPTT and attenuated increase of F1+2 after training. Resting levels of tPA- and PAI-Ag decreased slightly but not significantly after training. Exercise-induced changes were comparable after training in spite of higher power output in TR. Although the effects are small in healthy men, training modifies exercise-induced blood coagulation positively. The fact that exercise-induced changes in blood coagulation and fibrinolysis are rather attenuated or unchanged in the training group, in spite of a 20 % higher absolute power output during exercise, substantiates the adjusting effect of endurance training and the importance of physical fitness in primary prevention.