A phase II trial of second-line pemetrexed in adults with advanced/metastatic osteosarcoma

BackgroundOsteosarcoma is the most common primary malignant tumour in young adults. An effective treatment strategy for relapsed patients is still not defined. Pemetrexed is a multitargeted antifolate with a mode of action similar to, and a range of action broader than that of methotrexate. The primary objective of this phase II study was to determine tumour response rate in patients with high-grade, advanced/metastatic osteosarcoma. Secondary end-points included progression-free survival (PFS), overall survival (OS) and safety.MethodsPemetrexed 500 mg/m² was administered on day 1 of 21-day cycles with folic acid and vitamin B₁₂ supplementation. At least 5 tumour responses in a targeted population of 32 were required to consider further investigation.ResultsThirty-two patients (median age, 43.3 years; range, 18.6–76.0) with 1 prior chemotherapy regimen for high-grade advanced/metastatic osteosarcoma were enrolled. Thirty (93.8%) patients had an ECOG performance status ⩽1 and 29 (90.6%) had metastases in the lung. One patient had partial response (3.1%) and 5 (15.6%) had stable disease. Median PFS and OS were 1.4 months (95% CI: 1.4–1.7) and 5.5 months (95% CI: 2.3–10.5), respectively. The most common drug-related grade 3/4 toxicities were leukopaenia, asthaenia and elevated alanine aminotransferase in 3 (9.4%) patients each. One patient died due to multi-organ failure considered possibly related to the study drug.ConclusionsPemetrexed 500 mg/m² administered on day 1 of 21-day cycles as second-line treatment to patients with advanced/metastatic high-grade osteosarcoma was generally well tolerated but did not meet minimal response expectations for further investigation in this patient population.     

Sexually dimorphic postural adjustments during vertical behaviour are altered in a unilateral 6-OHDA rat model of Parkinson's disease

The study of sex differences in the onset, progression and symptoms of Parkinson's disease, in humans, has led to mixed results. In this study, we used a unilateral 6-hydroxydopamine (6-OHDA) lesion animal model of Parkinson's disease, to address whether there are sex differences in the composition of the movements used during vertical exploration within a confined cylinder. Tyrosine hydroxylase staining and apomorphine induced rotation were used to confirm lesion magnitude. There were no sex differences or lesion effects in the frequency of occurrence of a vertical bout or the average time spent vertical. Both male and female 6-OHDA animals exhibited equal impairments in the use of the forelimbs during vertical exploration. 6-OHDA males, as compared to 6-OHDA females, however, had a significant reduction in the use of their hindlimbs. An analysis of hindlimb step direction revealed that while sham females were more likely to step forward, sham males were more likely to step backwards during a vertical bout. This sex difference was no longer present in the 6-OHDA animals. Finally, 6-OHDA males were significantly more likely to place their dorsal surface in contact with the wall of the cylinder to maintain an upright posture during a vertical bout than animals in any other condition. These results demonstrate that the use of a confined cylinder task is appropriate for the kinematic analysis of sex differences in vertical behaviour and show that there are sex differences in motor behaviour in an animal model of human Parkinson's disease.     

Quantitative combination effects between sulforaphane and 3,3'-diindolylmethane on proliferation of human colon cancer cells in vitro

Isothiocyanates (ITCs) and indoles derived from cruciferous vegetables possess growth-inhibiting and apoptosis-inducing activities in cancer cell lines in vitro. ITCs like sulforaphane (SFN) are cytotoxic, whereas indoles including indole-3-carbinol or its condensation product 3,3'-diindolylmethane (DIM) are acting by cytostatic mechanisms in human colon cancer cell lines. In the present study, we have investigated the impact of defined combinations of SFN and DIM (ratio 1:4, 1:2, 1:1, 2:1 and 4:1) on cell proliferation, cell-cycle progression and apoptosis induction in cultured 40-16 colon carcinoma cells. Calculations of combination effects were based on the method of Chou et al. (1984) Adv. Enzyme Regul., 22, 27-55, and were expressed as a combination index (CI) with CI < 1, CI = 1 or CI > 1 representing synergism, additivity or antagonism, respectively. Interestingly, at a total drug concentration of 2.5 microM, all combinations of SFN and DIM were antagonistic. With increasing concentrations, the antagonistic effect gradually turned into a synergistic interaction at the highest combined cytotoxic concentration of 40 microM. Cell-cycle analyses with SFN:DIM ratios of 1:1, 1:2 and 1:4 and total concentrations between 10 and 25 microM confirmed antagonism at low and additive effects at higher doses. SFN (10 microM) in combination with DIM (10 microM) resulted in strong G(2)/M cell-cycle arrest, which was not observed with either compound alone. Our results indicate that cytotoxic concentrations of SFN:DIM combinations affect cell proliferation synergistically. At low total concentrations (below 20 microM), which are physiologically more relevant, the combined broccoli compounds showed antagonistic interactions in terms of cell growth inhibition. These data stress the need for elucidating mechanistic interactions for better predicting beneficial health effects of bioactive food components.     

Mild hyperhomocysteinemia is associated with a decreased fibrinolytic activity in patients after ST-elevation myocardial infarction

BACKGROUND: Elevated homocysteine (Hcy) levels have been associated with increased risk for cardiovascular disease and it has been shown that hyperhomocysteinemia is associated with increased levels of t-PA antigen in individuals without evidence for coronary artery disease (CAD). The aim of this study was to examine if Hcy plasma levels are associated with plasma levels of fibrinolytic factors in patients with CAD and a history of acute myocardial infarction. METHODS: We measured in 56 patients with CAD, 1 month after their first ST-elevation myocardial infarction, plasma levels of Hcy, the fibrinolytic parameters tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-type-1 (PAI-1), and t-PA-PAI-1 complexes. RESULTS: Hcy plasma levels inversely correlated with t-PA activity (r=-0.303, p<0.05). Patients with mild hyperhomocysteinemia (Hcy>15 micromol/L, n=8) showed significantly lower plasma levels of t-PA activity (p<0.05). Regression analysis revealed that out of cardiovascular risk factors and medical treatment only Hcy was significantly associated with t-PA activity. CONCLUSIONS: Patients with CAD after a first myocardial infarction and hyperhomocysteinemia show a reduced t-PA activity independently from cardiovascular risk factors and medical treatment. Homocysteine lowering therapies may increase fibrinolytic activity and thereby may help to avoid atherothrombotic events in patients with CAD after a first myocardial infarction.     

Differential effects on forelimb grasping behavior induced by fetal dopaminergic grafts in hemiparkinsonian rats

Skilled forelimb movements depend on an intact dopaminergic (DA) neurotransmission and are substantially impaired in the unilateral rat model of Parkinson's disease. It has remained unclear, however, to what extent reaching and grasping movements can be influenced by intrastriatal transplantation of fetal DA neurons. Here an extensive behavioral assessment of skilled forelimb movement patterns in hemiparkinsonian and DA-grafted rats was carried out. Good DA graft survival was accompanied by a compensation of drug-induced rotational asymmetries. Interestingly, skilled forelimb use was significantly improved in transplanted animals as compared to lesion-only animals in the staircase test. Qualitative analysis of single forelimb reaching movement components revealed dissociable patterns of graft effects: while some movement components in grafted animals improved, others remained unchanged or even deteriorated. These findings provide novel insights into the complex interactions of graft-derived restoration of DA neurotransmission and skilled forelimb behavior.     

TNM staging with FDG-PET/CT in patients with primary head and neck cancer

Purpose PET/CT, PET+CT, and CT were compared concerning accuracies in TNM staging and malignancy detection in head and neck cancer. The impact of PET/CT compared to the other imaging modalities on therapy management was assessed. Materials and methods Fifty-five patients with suspected head and neck primary cancer underwent whole-body FDG-PET/CT. PET/CT and PET+CT were evaluated by a nuclear medicine physician and a radiologist; CT was evaluated by two radiologists, PET by two nuclear physicians. Histopathology served as the standard of reference. Differences between the staging modalities were tested for statistical significance by McNemar’s test. Results Overall TNM-staging and T-staging with PET/CT were more accurate than PET+CT and CT alone (p < 0.05). PET/CT was marginally more accurate than CT alone in N-staging (p = 0.04); no statistically significant difference was found when compared to PET+CT for N-staging. PET/CT altered further treatment in 13 patients compared to CT only and in 7 patients compared to PET+CT. Conclusion Combined PET/CT proved to be partly more accurate in assessing the overall TNM-stage than CT and PET+CT. These results were based on a higher accuracy concerning the T-stage, mainly in patients with metallic implants and marginally the N-stage. Therapy decisions have been influenced in a substantial number of patients. PET/CT might be considered as a first line diagnostic tool in patients with suspected primary head and neck cancer.     

Factors associated with seeking medical care and submitting a stool sample in estimating the burden of foodborne illness

Laboratory-based surveillance is a foundation for public health and is essential for determining the incidence of most foodborne diseases caused by bacterial pathogens; however, reported cases represent a subset of infections in the community. To identify the factors associated with seeking medical care and submitting a stool specimen among persons with acute diarrheal illness, we used multivariate logistic regression to analyze data from two 12- month population-based telephone surveys conducted in the Foodborne Diseases Active Surveillance Network (FoodNet) from 2000 to 2003. Of 31,082 persons interviewed, 5% reported an acute diarrheal illness in the four weeks prior to the interview; of these, 20% sought medical care. On multivariate analysis, among persons with an acute diarrheal illness, factors associated with seeking medical care included: male sex; age <5 or >or=65 years; household income <25,000 dollars; having health insurance; diarrhea duration >or=3 days; having bloody diarrhea, fever, vomiting, sore throat, or cough. Of those seeking medical care, 19% provided a stool sample. Bloody diarrhea (odds ratio [OR] 3.35; 95% confidence interval [CI] 1.18-9.51) and diarrhea duration >or=3 days (OR 3.81; 95% CI: 1.50-9.69) were the most important factors associated with submission of a stool specimen. Cases of acute diarrheal illness ascertained through laboratory-based public health surveillance are likely to differ systematically from unreported cases and likely over-represent those with bloody diarrhea and longer diarrhea duration.     

Deaths due to unknown foodborne agents

This study reviews the available evidence on unknown pathogenic agents transmitted in food and examines the methods that have been used to estimate that such agents cause 3,400 deaths per year in the United States. The estimate of deaths was derived from hospital discharge and death certificate data on deaths attributed to gastroenteritis of unknown cause. Fatal illnesses due to unknown foodborne agents do not always involve gastroenteritis, and gastroenteritis may not be accurately diagnosed or reported on hospital charts or death certificates. The death estimate consequently omitted deaths from unknown foodborne agents that do not cause gastroenteritis and likely overstated the number of deaths from agents that cause gastroenteritis. Although the number of deaths from unknown foodborne agents is uncertain, the possible economic cost of these deaths is so large that increased efforts to identify the causal agents are warranted.