Dynamic 2-Deoxy-2-[<Superscript>18</Superscript>F]Fluoro-D-Glucose Positron Emission Tomography for Chemotherapy Response Monitoring of Breast Cancer Xenografts

Purpose

Non-invasive response monitoring can potentially be used to guide therapy selection for breast cancer patients. We employed dynamic 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography ([¹⁸F]FDG PET) to evaluate changes in three breast cancer xenograft lines in mice following three chemotherapy regimens.

Procedures

Sixty-six athymic nude mice bearing bilateral breast cancer xenografts (two basal-like and one luminal-like subtype) underwent three 60 min [¹⁸F]FDG PET scans. Scans were performed prior to and 3 and 10 days after treatment with doxorubicin, paclitaxel, or carboplatin. Tumor growth was monitored in parallel. A pharmacokinetic compartmental model was fitted to the tumor uptake curves, providing estimates of transfer rates between the vascular, non-metabolized, and metabolized compartments. Early and late standardized uptake values (SUV_E and SUV_L, respectively); the rate constants k ₁, k ₂, and k ₃, and the intravascular fraction v _B were estimated. Changes in tumor volume were used as a response measure. Multivariate partial least-squares regression (PLSR) was used to assess if PET parameters could model tumor response and to identify PET parameters with the largest impact on response.

Results

Treatment responders had significantly larger perfusion-related parameters (k ₁ and k ₂) and lower metabolism-related parameter (k ₃) than non-responders 10 days after the start of treatment. These findings were further supported by the PLSR analysis, which showed that k ₁ and k ₂ at day 10 and changes in k ₃ explained most of the variability in response to therapy, whereas SUV_L and particularly SUV_E were of lesser importance.

Conclusions

Overall, rate parameters related to both tumor perfusion and metabolism were associated with tumor response. Conventional metrics of [¹⁸F]FDG uptake such as SUV_E and SUV_L apparently had little relation to tumor response, thus necessitating full dynamic scanning and pharmacokinetic analysis for optimal evaluation of chemotherapy-induced changes in breast cancers.

     

BENIGN FAMILIAL NEONATAL CONVULSIONS

A family is reported where during the neonatal period convulsions have appeared in not less than 14 members in five generations. It appears to be an autosomal dominant trait. The disorder is benign and the convulsions have disappeared in the first weeks with a few exceptions, where sporadic convulsions have appeared up to 10 years of age. The etiology is at present unknown and there are no signs of disturbance in electrolyte or sugar balance or in amino-acid metabolism.     

Effect of cytochrome P450 isozyme induction and glutathione depletion on the metabolism of CS2 to TTCA in rats

 Analysis of 2-thiothiazolidine-4-carboxylic acid (TTCA), a metabolite of carbon disulfide (CS₂), is used in the biological monitoring exposure to CS₂ at work. In order to clarify the metabolic reasons for individual variation in the urinary excretion of TTCA, the latter was studied in rats pretreated with model cytochrome P450 (CYP) enzyme inducers or glutathione (GSH) depletors. Ethanol, phenobarbital (PB) or 3-methylcholanthrene (MC) did not increase 24-h TTCA output following CS₂ inhalation (50 or 500 ppm, 6 h). After oral dosing (10 mg/rat), PB had an inhibiting effect on the excretion rate of TTCA. Tissue GSH depletors phorone, L-buthionine-(RS)-sulfoximine (BSO) and diethylmaleate (DEM) decreased TTCA excretion in rats given an oral dose (10 mg/rat) of CS₂. The initial inhibition by phorone and DEM was reversed after 6 h and from 12 h onward the TTCA in urine exceeded the control level, an effect not seen with BSO. The proportion of CS₂ excreted in urine as TTCA within 24 h was 1.7% in control rats and 1% after BSO treatment, 1.3% after PB, 1.7% after acetone, 1.8% after MC, 2.0% after phorone and 2.5% after DEM treatment. The amount of TTCA in urine increased with the CS₂ dose in a non-linear fashion: 1.6 μmol (50 ppm/6 h) vs. 4.9 μmol (500 ppm/6 h), and 0.2 μmol (1 mg/kg) versus 3.6 μmol (100 mg/kg). It is concluded that induction of different cytochrome P450 isoforms and transient glutathione depletion have only minor effects on the disposition of TTCA in rats following low-level CS₂ exposure persistently low glutathione level as achieved by E.G. BSO, markedly decreased the metabolism of CS₂ to TTCA; these metabolic effectors are unlikely to have a major role in the individual variation of CS₂ metabolism in exposed workers. Received: 14 June 1994/Accepted: 25 August 1994     

Experimental modelling of drug membrane permeability by capillary electrophoresis using liposomes, micelles and microemulsions

Capillary electrophoresis (CE) was evaluated as an in-vitro format for experimental modelling of membrane permeability using only nanogram quantities of drug compounds. The rationale for the CE technique emanates from emulation of a lipid-like pseudo-stationary phase that governs separations mainly as a result of differences in molecular size, lipophilicity, hydrogen bonding and charge, all of which also have a strong influence on in-vivo drug absorption. By means of micellar, microemulsion and liposome electrolytes, the migration behaviour was studied at 37 degrees C for 22 model drug compounds. The generated CE retention factor data were then compared with membrane permeability reference data. Both simple log D and more common Caco-2 cell parameters were evaluated. In addition, permeation through intestinal segments of rat ileum and rat colon was included. An improved correlation was obtained in the order: micellar < microemulsion < liposome systems. Although the correlation for the best liposome CE system was only R(2)=0.77, the evaluation results for all emphasized the strength and flexibility of CE for assessing specific drug-membrane interaction through tailor-made lipophilic media.     

Assessment of soil remediation workers' exposure to polycyclic aromatic hydrocarbons (PAH): biomonitoring of naphthols, phenanthrols, and 1-hydroxypyrene in urine

Urinalysis of multiple polycyclic aromatic hydrocarbons (PAH) biomarkers has been applied to assess the exposure of soil remediation workers on a former creosote wood impregnation site polluted with creosote oil. The uptake of PAHs was measured in preshift, end-of-shift, evening, and next preshift specimens (n=33) of nine volunteers with diverse tasks, using sensitive HPLC-FD methods. The ranges of biomarker concentrations in urine (nmol/l) were: 1-naphthol (14-159), 2-naphthol (9-166), 1- plus 2-naphthol (35-269), 1-hydroxyphenanthrene (OHPhe) (6-56), 2- plus 3-OHPhe (6-70), 4-OHPhe (1-6), 9-OHPhe (1-7), the sum of phenanthrols (15-135), and 1-hydroxypyrene, OHP (2.2-67). Eight of nine workers had OHP levels higher than the Finnish biological limit value for non-occupationally exposed persons (3nmol/l). A linear correlation was observed between 1- and 2-naphthol (r=0.90). The biomarker OHP correlated well in urine both with the major (1-OHPhe, r=0.96; 2- plus 3-OHPhe, r=0.84) and the minor phenanthrene metabolites (4-OHPhe, r=0.77; 9-OHPhe, r=0.68), and with the sum of all phenanthrols (r=0.94), but not so well with the sum of naphthols (r=0.66, p<0.001). The smokers had 2.9-, 2.2-, and 4.8-fold higher average concentrations of naphthols, phenanthrols, and OHP, respectively, than the non-smokers. The PAH biomarker data (concentrations and diurnal excretion profiles) showed significant work-related exposure in both non-smoking and smoking subjects. The average exposure levels were clearly higher than those we have measured for instance in asphalt paving workers. The workers' exposure should be assessed by biological monitoring, because at this type of outdoor work the dermal and pulmonary uptake of PAHs are both likely. Adequate measures for preventing, particularly, dermal absorption are of crucial importance for reducing the workers' risk of exposure to carcinogens on soil remediation sites.     

Food Hypersensitivity in Patients with Pollen Allergy

Six hundred patients with pollen allergy answered a questionnaire about food hypersensitivity. Hypersensitivity to various nuts, fruits and roots was reported more often by patients with birch pollen allergy(70%) than be patients without birch pollen allergy (19%). The stronger the skin test reaction to birch pollen, the higher was the incidence of food hypersensitivity. A negative correlation was found between grass pollen allergy and food hypersensitivity.
In the diagnosis of springtime hayfever, the presence of hypersensitivity to nuts, fruits and roots supports a diagnosis of birch pollen allergy.     

Inadequate symptom control in advanced cancer patients across Europe

Purpose  

The purpose of this study is to examine the adequacy of treatment for constipation, nausea, depression and poor sleep and the factors associated with inadequate symptom control in cancer patients receiving opioids.     

Interpreting trends in prostate cancer incidence and mortality in the five Nordic countries

Trends in incidence and mortality rates of prostate cancer were analyzed using data from the national cancer registries of Denmark, Finland, Iceland, Norway, and Sweden. Joinpoint regression models were used to quantify temporal trends for the period from 1980 to 2004. Incidence rates were increasing and similar in the Nordic countries during the 1980s. Around 1990, a more rapid incidence increase began in all Nordic countries except Denmark, where an increase was seen 5 years later. In 2001, incidence rates in Denmark were half of those seen in the other Nordic countries, but mortality rates varied only marginally among countries. Mean annual declines in prostate cancer mortality of 1.9% (95% CI = 0.4% to 3.3%) and 1.8% (95% CI = 0.5% to 3.0%) were observed from 1996 to 2004 in Finland and Norway, respectively. During the same period, mortality rates leveled off in Iceland and Sweden but continued to increase in Denmark. The rapid increase in incidence during the early 1990s coincided with the introduction of the prostate-specific antigen (PSA) test and conveys little information about the occurrence of potentially lethal disease. Mortality rates, however, have recently stabilized or declined in countries where PSA testing and curative treatment have been commonly practiced since the late 1980s. Although other explanatory factors may be in operation, these trends are consistent with a moderate effect of increased curative treatment of early diagnosed prostate cancer and improved treatment of more advanced disease.     

A prospective pilot study of a multidisciplinary home training programme for lateral epicondylitis

Objective: To evaluate a new multidisciplinary structured home training programme for patients with lateral epicondylitis compared to conventional attendance. Design: This study utilized a prospective non‐randomized design to compare the effect of a home exercise programme against a pragmatic approach to managing patients with lateral epicondylitis in a primary care setting in Sweden. Subjects: A total of 78 patients, presenting to their general practitioner with lateral epicondylitis were recruited from two separate geographical areas. The patients were divided into two group, 51 entered the intervention group and 27 entered the control group. Methods: The intervention group was treated with a specific home training programme, ergonomic advice and when necessary wrist and/or night bandages. The control group was treated with conventional treatment, e.g. corticosteroid injections, stretching or no intervention. Pain and function were evaluated by the PRFEQ. An electronic hand‐power gauge measured strength and stamina. Sick‐leave absence was collected via the regional Social Insurance Office. Results: After four weeks the intervention group experienced less sick‐leave, less pain, better function and returned to work earlier than the control group. After 16 weeks the intervention group still had significantly better function than the control group and were taking less sick‐leave. Pain decreased more in the intervention group but this was not significant. There was no difference in grip strength between the two groups. Conclusion: A structured home training programme can improve function and reduce sick leave in patients with lateral epicondylitis. Copyright © 2006 John Wiley & Sons, Ltd.     

Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC

Here we provide the updated version of the guidelines of the European Association for Palliative Care (EAPC) on the use of opioids for the treatment of cancer pain. The update was undertaken by the European Palliative Care Research Collaborative. Previous EAPC guidelines were reviewed and compared with other currently available guidelines, and consensus recommendations were created by formal international expert panel. The content of the guidelines was defined according to several topics, each of which was assigned to collaborators who developed systematic literature reviews with a common methodology. The recommendations were developed by a writing committee that combined the evidence derived from the systematic reviews with the panellists' evaluations in a co-authored process, and were endorsed by the EAPC Board of Directors. The guidelines are presented as a list of 16 evidence-based recommendations developed according to the Grading of Recommendations Assessment, Development and Evaluation system.