Semi-extended, six weekly rituximab infusions in pre-treated advanced low-grade B cell non-Hodgkin's lymphoma: a phase II study

Either four or eight weekly rituximab infusions in relapsed or refractory low-grade or follicular B cell non-Hodgkin's lymphoma (NHL) are well tolerated and efficacious. This phase II trial investigated the safety and efficacy of six weekly rituximab doses in chemotherapeutically pre-treated relapsed or refractory low-grade NHL patients. Sixty-eight patients (median age 64 years) received six i.v. rituximab infusions 375 mg/m2 weekly. All patients had received one or more prior therapies (median 2; range 1-18). Forty-two patients had progressive disease and were evaluated for toxicity and efficacy; 12 of these required re-treatment with six weekly rituximab infusions. Twenty-six patients received rituximab as remission consolidation therapy and were assessed for toxicity only. No patients discontinued because of adverse events. Most adverse events were National Cancer Institute grade 1 (2-9%) or 2 (3-5%) and usually occurred during the first infusion. No hematological abnormalities were observed. Overall response rate was 59% (median time to response 2 weeks) and 10 of 12 re-treated patients responded. Median time to progression for all patients was 14 months and for responders 21 months. More than half the 42 patients evaluated for efficacy and more than 70% of the 25 responding patients still survived longer than 3 years after treatment. The safety profile and efficacy achieved in this study compare favorably with those seen with four or eight weekly doses in pre-treated low-grade NHL.     

Assessment of neonatal tetanus elimination in an African setting by lot quality assurance cluster sampling (LQA-CS)

Neonatal tetanus (NT) elimination, < 1 case per 1,000 live births (LB), was assessed at district level in Zimbabwe using a combined lot quality assurance-cluster sampling survey (LQA-CS). Three of the highest risk districts were selected. NT was considered eliminated if fewer than a specified number of NT deaths (proxy for NT cases) were found in the sample determined using operating characteristic curves and tables. TT2 + vaccine coverage was measured in mothers who gave birth 1-13 months before the survey and women aged 15-49 years. NT was considered as eliminated, TT2+ coverage was 78% (95% CI 71-82%) in women aged 15-49 and 83% (95% CI 76-89%) in mothers. The survey cost 30,000 US dollars excluding costs of consultants. NT incidence was below the elimination threshold (< 1/1,000 LB) in the surveyed districts and probably in all districts. LQA-CS is a practical, relatively cost effective field method which can be applied in an African setting to assess NT elimination status.     

Fluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imaging

A recent development in biomedical imaging is the non-invasive mapping of molecular events in intact tissues using fluorescence. Underpinning to this development is the discovery of bio-compatible, specific fluorescent probes and proteins and the development of highly sensitive imaging technologies for in vivo fluorescent detection. Of particular interest are fluorochromes that emit in the near infrared (NIR), a spectral window, whereas hemoglobin and water absorb minimally so as to allow photons to penetrate for several centimetres in tissue. In this review article we concentrate on optical imaging technologies used for non-invasive imaging of the distribution of such probes. We illuminate the advantages and limitations of simple photographic methods and turn our attention to fluorescence-mediated molecular tomography (FMT), a technique that can three-dimensionally image gene expression by resolving fluorescence activation in deep tissues. We describe theoretical specifics, and we provide insight into its in vivo capacity and the sensitivity achieved. Finally, we discuss its clinical feasibility. Electronic Publication     

Optical-based molecular imaging: contrast agents and potential medical applications

Laser- and sensitive charge-coupled device technology together with advanced mathematical modelling of photon propagation in tissue has prompted the development of novel optical imaging technologies. Fast surface-weighted imaging modalities, such as fluorescence reflectance imaging (FRI) and 3D quantitative fluorescence-mediated tomography have now become available [1, 2]. These technical advances are paralleled by a rapid development of a whole range of new optical contrasting strategies, which are designed to generate molecular contrast within a living organism. The combination of both, technical advances of light detection and the refinement of optical contrast media, finally yields a new spectrum of tools for in vivo molecular diagnostics. Whereas the technical aspects of optical imaging are covered in more detail in a previous review article in "European Radiology" [3], this article focuses on new developments in optical contrasting strategies and design of optical contrast agents for in vivo diagnostics. Electronic Publication     

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

Mutations of the BRCA1 or BRCA2 genes have been shown to strongly predispose towards the development of contralateral breast cancer in patients from large multi-case families. In order to test the hypothesis that BRCA1 and BRCA2 mutations are more frequent in patients with bilateral breast cancer, we have investigated a hospital-based series of 75 consecutive patients with bilateral breast cancer and a comparison group of 75 patients with unilateral breast cancer, pairwise matched by age and family history, for mutations in the BRCA1 and BRCA2 genes. Five frameshift deletions (517delGT in BRCA1; 4772delA, 5946delCT, 6174delT and 8138del5 in BRCA2) were identified in patients with bilateral disease. No further mutations, apart from polymorphisms and 3 rare unclassified variants, were found after scanning the whole BRCA1 and BRCA2 coding sequence. Three pathogenic BRCA1 mutations (Cys61Gly, 3814del5, 5382insC) were identified in the group of patients with unilateral breast cancer. The frequencies of common BRCA1 and BRCA2 missense variants were not different between the 2 groups. In summary, we did not find a significantly increased prevalence of BRCA1 and BRCA2 mutations in a hospital-based cohort of German patients with bilateral breast cancer. We conclude that bilaterality of breast cancer on its own is not strongly associated with BRCA1 and BRCA2 mutations when adjusted for age and family history. The high frequency of bilateral disease in multi-case breast cancer families may be due to a familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 and BRCA2 mutations.     

Die p-Tyramin-Ausscheidung im Urin

Zusammenfassung Die Ausscheidung von freiem p-Tyramin im Urin wurde bei Kindern verschiedener Altersklassen fluorimetrisch nach der Methode von Oates bestimmt.Die Ausscheidung der Säuglinge betrug 1,97±0,75 g/mg Kreatinin, die der Kleinkinder 1,18±0,77 g/mg Kreatinin. Die p-Tyraminausscheidung von unreifen und reifen Neugeborenen schwankte stärker; ihre Ausscheidung lag aber in derselben Größnordnung, wenn keine Hypertyrosinämie vorlag.Bei Kindern mit Eiweißverwertungsstörungen des Darmes (Mucoviscidose und Cöliakie) war die Ausscheidung mit 3,16±1,98 g/mg Kreatinin signifikant erhöht. Keine Erhöhung der p-Tyraminausscheidung fand sich bei Säuglingen mit Toxikose auf dem Boden einer Enteritis.Die Ergebnisse werden im Rahmen der heutigen Kenntnisse über die Bildung und Ausscheidung von p-Tyramin diskutiert.

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Summary The urinary excretion of p-tyramine was fluorometrically estimated in children of different ages according to the method of Oates.The amount excreted was 1.97±0.77 g per mg. creatinine in infants and 1.18±0.77 g per mg. creatinine in children. If there is no hypertyrosinaemia in immature and mature newborns the excretion of p-tyramine fluctuates to a greater extent especially in the range of lower limits.Children with desturbed protein digestion (cystic fibrosis and coeliac disease) had a significantly increased excretion of p-tyramine (3.16±1.98 g per mg. creatinine). No elevation of p-tyramine excretory rates was in infants with severe enteritis. The results are discussed together with our present-day knowledge on synthesis and excretion of p-tyramine.

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Mit Unterstützung durch die Deutsche Forschungsgemeinschaft.     

Amine im menschlichen Stuhl

Zusammenfassung Die p- und m-Tyraminausscheidung wurde quantitativ im Stuhl von Neugeborenen, Säuglingen und Schulkindern unter verschiedenen Kostformen untersucht. Der p-Tyramingehalt von normalen Säuglingsstühlen (Naßgewicht) lag zwischen 0,030–0,460 Mol/g Stuhl, der normaler Stühle von Schulkindern zwischen 0,005 und 0,102 Mol/g Stuhl. m-Tyramin ließ sich in Säuglingsstühlen nicht nachweisen. Die Konzentration im Stuhl von Schulkindern überschritt sicher nicht 0,008 Mol/g Stuhl.

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Summary The excretion of para- and meta-tyramine in faeces was estimated in newborns, infants, and children during the application of various diets. The p-tyramine content of normal stools of infants (wet weight) amounted 0.030–0.460 moles per gr. faeces and that of children 0.005–0.102 moles per gr. m-Tyramine was not detected in the faeces of infants. If this substance is found at all in faeces of children it does not exceed 0.008 moles per gr. of faeces.

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Mit Unterstützung durch die Deutsche Forschungsgemeinschaft.     

Development of prediction models for three in vitro embryotoxicity tests in an ECVAM validation study

Since 1997 the National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments, ZEBET, in Berlin, has been coordinating a validation study aimed at prevalidation and validation of three in vitro embryotoxicity tests, funded by the European Center for the Validation of Alternative Methods (ECVAM) at the Joint Research Center (JRC, Ispra, Italy). The tests use the cultivation of postimplantation rat whole embryos (WEC test), cultures of primary limb bud cells of rat embryos (micromass or, MM, test), and cultures of a pluripotent mouse embryonic stem cell line (embryonic stem cell test or EST). Each of the tests was performed in four laboratories under blind conditions. In the preliminary phase of the validation study 6 out of 20 test chemicals comprising different embryotoxic potential (non, weakly, and strongly embryotoxic) were tested. The results were used to define biostatistically based prediction models (PMs) to identify the embryotoxic potential of test chemicals for the WEC test and the MM test. The PMs developed with the results of the preliminary phase of the validation study (training set) will be evaluated with the results of the remaining 14 test chemicals (definitive phase) by the end of the study. In addition, the existing, improved PM (iPM) for the EST, which had been defined previously, was evaluated using the results of the preliminary phase of this study. Applying the iPM of the EST to the results of this study, in 79% of the experiments, chemicals were classified correctly according to the embryotoxic potential defined by in vivo testing. For the MM and the WEC test, the PMs developed during the preliminary phase of this validation study provided 81% (MM test) and 72% (WEC test) correct classifications. Because the PM of the WEC test took into account only parameters of growth and development, but not cytotoxicity data, a second PM (PM2) was developed for the WEC test by incorporating cytotoxicity data of the differentiated mouse fibroblast cell line 3T3, which was derived from the EST. This approach, which has previously never been used, resulted in an increase to 84% correct classifications in the WEC test.     

Selenium content of human milk,cow's milk and cow's milk infant formulas

The selenium content of human milk, cow's milk and cow's milk infant formula were estimated by instrumental neutron activation analysis. The highest values were found in 3 samples of human colostrum (524–865×10^-9 g/g dry weight). There was a significant decrease with increasing time post partum. Mature human milk exhibited a selenium content of 230±79×10^-9 g/g dry weight.The selenium content of 45 samples of cow's milk from the north-western area of Germany was 200±39×10^-9 g/g dry weight. While there was no significant difference between the values of mature human milk and of cow's milk, cow's milk infant formula exhibited significantly (P<0.01) lower values than human milk. The average selenium content of 107 samples of 10 different commercially available fluid and powdered cow's milk infant formulas (range: 18–171×10^-9 g/g dry weight) amounted to about only one third of that in mature human milk.With support of the Deutsche Forschungsgemeinschaft