Phytotoxicity of organic extracts of five medicinal plants of the Neotropical savanna.

Medicinal plants produce a high diversity of secondary metabolites with different biological activities, which are commonly evaluated when prospecting for bioherbicides. We analyzed the phytotoxic activity of organic extracts from the leaves of five medicinal species, Byrsonima intermedia, Moquiniastrum polymorphum, Luehea candicans, Miconia chamissois, and Qualea cordata. Phytotoxicity was evaluated on the initial growth of cucumber seedlings through tests with different concentrations of hexane, ethyl acetate, and methanol extracts. The results showed that all organic extracts and all concentrations affected cucumber development, with methanol extracts generally showing the greatest negative effect on the initial growth of the target species. The only exception was for M. chamissois extracts, in which the hexane extract had the greatest phytotoxicity. Furthermore, the organic extracts were subjected to preliminary phytochemical analysis, revealing the widespread presence of alkaloids along with other chemical classes. All the study species are thus potential candidates for use as natural herbicides.

A novel function of HER2/Neu in the activation of G2/M checkpoint in response to γ-irradiation.

In response to γ-irradiation (IR)-induced DNA damage, activation of cell cycle checkpoints results in cell cycle arrest, allowing time for DNA repair before cell cycle re-entry. Human cells contain G1 and G2 cell cycle checkpoints. While G1 checkpoint is defective in most cancer cells, commonly due to mutations and/or alterations in the key regulators of G1 checkpoint (for example, p53, cyclin D), G2 checkpoint is rarely impaired in cancer cells, which is important for cancer cell survival. G2 checkpoint activation involves activation of ataxia telangiectasia-mutated (ATM)/ATM- and rad3-related (ATR) signalings, which leads to the inhibition of Cdc2 kinase and subsequent G2/M cell cycle arrest. Previous studies from our laboratory show that G2 checkpoint activation following IR exposure of MCF-7 breast cancer cells is dependent on the activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signaling. As HER receptor tyrosine kinases (RTKs), which have important roles in cell proliferation and survival, have been shown to activate ERK1/2 signaling in response to various stimuli, we investigated the role of HER RTKs in IR-induced G2/M checkpoint response in breast cancer cells. Results of the present studies indicate that IR exposure resulted in a striking increase in the phosphorylation of HER1, HER2, HER3 and HER4 in MCF-7 cells, indicative of activation of these proteins. Furthermore, specific inhibition of HER2 using an inhibitor, short hairpin RNA and dominant-negative mutant HER2 abolished IR-induced activation of ATM/ATR signaling, phosphorylation of Cdc2-Y15 and subsequent induction of G2/M arrest. Moreover, the inhibition of HER2 also abrogated IR-induced ERK1/2 phosphorylation. In contrast, inhibition of HER1 using specific inhibitors or decreasing expression of HER3 or HER4 using short hairpin RNAs did not block the induction of G2/M arrest following IR. These results suggest an important role of HER2 in the activation of G2/M checkpoint response following IR.

X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis.

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.

Avaliação do potencial alelopático, atividade antimicrobiana e antioxidante dos extratos orgânicos das folhas de Pyrostegia venusta (Ker Gawl. ) Miers (Bignoniaceae) / Evaluation of allelopathic potential, antimicrobial and antioxidant activities of Pyrostegia venusta (Ker Gawl. ) Miers (Bignoniaceae) leaf organic extracts

Este trabalho apresenta os resultados de atividade alelopática, antimicrobiana e antioxidante dos extratos orgânicos (hexano, acetato de etila e metanol) das folhas de Pyrostegia venusta (Ker Gawl.) Miers (Bignoniaceae). Para alelopatia, foi estudado o desenvolvimento de Cucumis sativus (pepino), sendo avaliados o comprimento da raiz principal, o número de raízes secundárias e o comprimento do hipocótilo. Os dois primeiros parâmetros foram afetados por todos os três extratos testados enquanto o comprimento do hipocótilo só não foi afetado pelo extrato acetato de etila. Quanto à atividade antimicrobiana, avaliada pelo ensaio de CIM, o extrato hexânico apresentou inibição moderada frente ao Staphylococcus aureus (0,9 mg mL-1) e forte ao Enterococcus hirae (0,5 mg mL-1). O extrato acetato de etila apresentou forte atividade frente Candida albicans (0,3 mg mL-1) enquanto o extrato metanólico não mostrou-se ativo para os microrganismos testados. Por outro lado, o extrato metanólico apresentou a maior capacidade de seqüestrar radicais livres (Concentração Efetiva 50 por cento-CE50 =102,0 ± 56,9 mg mL-1, com TCE50 = 30 min) no ensaio com DPPH (2,2-difenil-1-picril-hidrazila) e o maior teor de compostos fenólicos (116,2 ± 83,0 mg ácido gálico g amostra-1), avaliado pelo ensaio de Folin-Ciocalteau.

This paper presents the results of allelopathic, antimicrobial and antioxidant activities of organic extracts (hexane, ethyl acetate and methanol) from the leaves of Pyrostegia venusta (Ker Gawl.) Miers (Bignoniaceae). Allelopathic activity was assessed based on Cucumis sativus (cucumber) development for the parameters main root length, number of secondary roots and hypocotyl length. All tested extracts affected the first two parameters, while the hypocotyl length was not affected only by the ethyl acetate extract. For antimicrobial activity, assessed by MIC assay, hexane extract showed moderate inhibition for Staphylococcus aureus (0.9 mg mL-1) and strong inhibition for Enterococcus hirae (0.5 mg mL-1). Ethyl acetate extract showed strong activity against Candida albicans (0.3 mg mL-1), whereas methanolic extract was not active against the tested microorganisms. On the other hand, methanol extract showed the most promising radical scavenging capacity (Effective Concentration 50 percent - EC50 = 102.0 ± 56.9 mg mL-1, with TEC50 = 30 min) in DPPH assay (2,2-diphenyl-1-picryl-hidrazil) and the highest level of phenolic compounds (116.2 ± 83.0 mg acid garlic g sample-1), as indicated by Folin-Ciocalteau assay.

[Regional coordination of paediatric oncological care in northwestern Lower Saxony, Germany--network funded by health insurance companies]. / Verbund PädOnko Weser-Ems--Regionale ambulante Versorgung pädiatrisch-onkologischer Patienten aus der Weser-Ems-Region im Rahmen einer Integrierten Versorgung.

The cure rates in pediatric oncology have been substantially improved due to standardized treatment strategies and centralization of therapy. Close clinical and hematological monitoring is mandatory for patients between periods of chemotherapy for early detection and treatment of therapy-related complications such as infections. This results in frequent and time-consuming outpatient examinations for the patient and family at the oncological center in order to evaluate clinical condition and hematological findings. In widespread regions such as the Weser-Ems area in northwest Lower Saxony, Germany, the long distances between patients' home and the oncological center lead to higher risks and impairment of quality of life (QoL) for the patients and their families. Accordingly, in 2001 pediatric hospitals and practices, patient care services and patients' support groups in Weser-Ems founded a network (Verbund PädOnko Weser-Ems). The "Verbund PädOnko" aims at coordinated, high-quality regional outpatient patient treatment in order to reduce risks of long-distance transports to reach the oncological center. Since 2005 a newly established mobile care team realized 1 443 home visits covering a total of 150 300 km. Since 2007 the network has been funded by health insurance organisations. Internal and external benchmarking was performed showing that the rate of short term inpatient treatments were reduced. Treatment quality was assured and the QoL of the patients and their families was improved through the work of the network. The "Verbund PädOnko Weser-Ems" network represents a promising prototype model for the regional coordination of outpatient treatment and care of patients with rare diseases in wide spread areas.

Análise de crescimento e anatomia foliar da planta medicinal Ageratum conyzoides L. (Asteraceae) cultivada em diferentes substratos / Growth analysis and leaf anatomy of the medicinal plant Ageratum conyzoides L. (Asteraceae) grown on different substrates

Ageratum conyzoides L. (Asteraceae) é uma espécie herbácea que ocorre em áreas de cerrado e, por se tratar de planta medicinal, é cultivada em escala familiar. O objetivo deste trabalho foi estudar possíveis alterações no desenvolvimento das plantas quando cultivadas em solos com texturas diferentes (solo de cerrado, franco arenoso ou solo de terra roxa, muito argiloso). Foram analisados aos 40, 70 e 90 dias, o comprimento do caule e da raiz, massa seca da parte aérea (caule e folhas) e das raízes, número de folhas e área foliar; além de parâmetros anatômicos foliares, como a densidade de tricomas. Os resultados mostraram que os comprimentos do caule e da raiz aumentaram no decorrer do experimento, independentemente do substrato (com exceção do comprimento da raiz de plantas cultivadas em solo de terra roxa). Porém, o comprimento do caule foi sempre maior nas plantas cultivadas em solo de cerrado, enquanto o comprimento da raiz foi significativamente maior somente aos 90 dias de cultivo neste solo. As biomassas secas da raiz e do caule também foram maiores nas plantas cultivadas em solo de cerrado por 70 e 90 dias, respectivamente. A massa seca foliar foi maior nas plantas cultivadas em solo de cerrado a partir dos 70 dias de experimento. Esse aumento foi devido ao maior número de folhas produzidas e a maior área foliar dessas plantas. No geral, a anatomia foliar não diferiu, porém o número de tricomas glandulares foi maior nas plantas cultivadas em solo de cerrado. Os resultados indicaram que esta espécie tem melhor desenvolvimento quando cultivada em solo mais arenoso.

Ageratum conyzoides L. (Asteraceae) is a herbaceous species found in cerrado areas and grown in family scale since it is a medicinal plant. The aim of this work was to study possible alterations in the plant development when grown in soils presenting different textures (a sandy-loam cerrado soil, or a very clayish red earth soil). At 40, 70 and 90 days, stem and root length, shoot (stem and leaves) and root dry matter, number of leaves and leaf area were evaluated, in addition to leaf anatomical parameters, such as trichome density. Stem and root length increased over the experiment under any substrate (except root length of plants grown on red earth soil). However, stem length was always higher in plants grown on cerrado soil, whereas root length was significantly higher only at 90 days of cultivation on this same soil. Root and stem dry biomass were also higher in plants grown on cerrado soil at 70 and 90 days, respectively. Leaf dry matter was higher in plants grown on cerrado soil from 70 days of experiment. This increase was due to the larger number of produced leaves and the higher leaf area of those plants. In general, leaf anatomy does not differ; however, the number of glandular trichomes was larger in plants grown on cerrado soil. Such results indicated that this species had a better development when grown on sandier soils.

Protein phosphatase 2A has an essential role in the activation of gamma-irradiation-induced G2/M checkpoint response.

G2/M checkpoint activation after DNA damage results in G2/M cell cycle arrest that allows time for DNA repair before the entry of cells into mitosis. Activation of G2/M checkpoint involves a series of signaling events, which include activation of ataxia telangiectecia-mutated and Rad3-related (ATR) and Chk1 kinases and inhibition of Cdc2/Cyclin B activity. Studies presented in this report show that serine (Ser)/threonine (Thr) protein phosphatase 2A (PP2A) has an important role in G2/M checkpoint activation in response to gamma-irradiation (IR) exposure. Using PP2A inhibitors, as well as siRNA targeting various forms of Ser/Thr protein phosphatases, results presented in this report show that specific PP2A inhibition abrogates IR-induced activation of ATR and Chk1 kinases, as well as phosphorylation of Cdc2-Tyr15, and attenuates IR-induced G2/M arrest. These results suggest an important regulation of PP2A on IR-induced G2/M checkpoint signaling response.

Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer.

BACKGROUND: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. PATIENTS AND METHODS: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m(2), day 1) and vinorelbine (25 mg/m(2) on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m(2), followed by 250 mg/m(2) weekly thereafter). RESULTS: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. CONCLUSION: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone.

First experiences with laparoscopic adjustable gastric banding (LAGB) in the treatment of patients with childhood craniopharyngioma and morbid obesity.

Craniopharyngiomas are embryogenic malformations which lead to eating disorders and morbid obesity due to hypothalamic involvement in about 50% of all patients with pediatric craniopharyngioma. The experience with laparoscopic adjustable gastric banding (LAGB) in obese craniopharyngioma patients is limited. We are reporting on four patients with childhood craniopharyngioma diagnosed at age 2, 11, 12, and 21 years. BMI-SDS at diagnosis was +0.9, +4.5, +4.7 and -0.1 SD. During follow-up, all patients developed morbid obesity (BMI-SDS: +13.9, +10.3, +11.4, +7.3) so that 11, 6, 9 and 3 years after diagnosis LAGB were performed. After a follow-up of 4.5, 1.5, 3.0 and 2.5 years BMI decreased or stabilized continuously in all patients (BMI-SDS at latest visit: +9.9, +9.7, +9.5, +5.9 SD). The eating behavior changed in all patients profoundly. The addiction to food and especially sweets significantly improved based on self-assessment. In two patients a dislocation of the LAGB occurred and resulted in weight gain. We conclude that LAGB could be effective in weight reduction of obese craniopharyngioma patients with hypothalamic syndrome. Close follow-up is necessary in order to analyze long-term effects and complications of LAGB in patients with childhood craniopharyngioma and morbid obesity.

Relapse pattern after complete resection and early progression after incomplete resection of childhood craniopharyngioma.

In HIT Endo data on therapy and prognosis of 306 patients with childhood craniopharyngioma (CP) were analyzed. The 5 years-overall survival rate was 94 +/- 4 % in irradiated patients and 93 +/- 5 % in non-irradiated patients. Aims of the prospective study KRANIOPHARYNGEOM 2000 were to collect data on the incidence and time course of relapses after complete surgery and tumour progressions after incomplete resection. Furthermore, the impact of irradiation therapy (XRT) on tumour relapse and recurrence rates was analyzed. Since 2001 ninety-eight patients with CP were recruited at a median age at diagnosis of 9.9 years ranging from 1.8 to 18.0 years. Complete resection was achieved in 44 %, incomplete resection in 54 %. XRT was performed in 24 of 98 CP patients; in 10 early after incomplete resection, in 14 of 24 after progression of residual tumour or relapse, in 3 of 14 after second surgery of relapse. XRT was performed at a median age of 12.0 years ranging from 5.0 to 18.9 years and in median after an interval of 9 months after first diagnosis. The analysis of event-free survival rates (EFS) in patients with CP showed a high rate of early events in terms of tumour progression after incomplete resection (3y-EFS: 0.22 +/- 0.09) and relapses after complete resection (3y-EFS: 0.60 +/- 0.10) during the first three years of follow-up. A high rate of early events (1y-EFS: 0.78 +/- 0.10; 2y-EFS: 0.57 +/- 0.15) was also found for patients after XRT (3 cystic progressions, 3 progressions of solid tumour; in 24 patients after XRT). We conclude that tumour progression and relapse are frequent and early events even in irradiated patients. Monitoring of cerebral imaging and clinical status is recommended in follow-up of patients with childhood CP. In order to analyze the appropriate time point of XRT after incomplete resection, QoL, EFS and overall survival in patients (age > or = 5 years) will be analyzed in KRANIOPHARYNGEOM 2007 after stratified randomization of the time point of irradiation after incomplete resection (early irradiation versus irradiation at progression of residual tumour).

Prognosis and sequela in patients with childhood craniopharyngioma -- results of HIT-ENDO and update on KRANIOPHARYNGEOM 2000.

The overall survival rate of patients with craniopharyngioma, an embryogenic malformation, is high (0.92 +/- 0.03). However, there is considerable morbidity and impaired quality of life, even when the tumor can be completely resected. Aim of our study was to analyze risk factors for severe obesity (body mass index [BMI] > or = 7 SD) and the prognosis of severely obese survivors of childhood craniopharyngioma recruited in our cross-sectional study on 183 patients (HIT-ENDO) and in the prospective study KRANIOPHARYNGEOM 2000. Severe obesity (BMI > or = 7 SD) was present in 16 % of patients and associated with higher tumor volume (p < 0.05), more frequent neurosurgical interventions (p < 0.05) and a higher rate of hypothalamic involvement (p < 0.001). Self-assessed functional capacity (FMH) was lower (p < 0.001) in severely obese survivors (FMH: median 33, range: 4-64) when compared with normal weight patients (FMH: 50; 1-95). Overall survival (20 years) was lower (p = 0.034) in patients with severe obesity in comparison to patients with moderate obesity and normal weight. Cardiovascular morbidity and mortality was high in severely obese patients. Between 10/01 and 03/04 fifty-seven patients (27 female/30 male) were recruited in KRANIOPHARYNGEOM 2000 (www.kraniopharyngeom.com). The impact of tumor localization (3.2 % intrasellar, 22.6 % suprasellar, 74.2 % combined intra/suprasellar; 51.6 % hypothalamic involvement) and treatment (26 complete resections, 22 partial resections followed by irradiation in one case; primary irradiation after biopsy in one case) on quality of life, functional capacity and prognosis will be evaluated longitudinally and prospectively.

CNS disease as the main manifestation of hemophagocytic lymphohistiocytosis in two children.

Hemophagocytic lymphohistiocytosis is a rare and fatal disorder of early infancy, which affects predominantly the mononuclear phagocyte system and is characterized by the presence of fever, hepatosplenomegaly and cytopenia. Neurological symptoms can be extremely variable, ranging from irritability, and convulsions to focal neurological signs. They often develop during disease progression, but can also be the leading initial symptoms. Early diagnosis is mandatory, because new treatments, including bone marrow transplantation, appear to be promising. Here we present the clinical, neuroradiological and histopathological findings from two children with progressive CNS disease as the main clinical manifestation of hemophagocytic lymphohistiocytosis. Both children died and diagnosis was only obtained in retrospect after careful review of the histopathological material.

Effects of anoxia on root ultrastructure of four neotropical trees.

The root ultrastructure of seedlings grown in anaerobic conditions was investigated in four neotropical species: Sesbania virgata, Erythrina speciosa, Sebastiania commersoniana (all present in waterlogged or flooded areas), and Schizolobium parahyba (that occupies mainly dry areas). Anaerobiosis induced an increase in the size of mitochondria, dilatation of cristae and of the endoplasmic reticulum, and fragmentation or concentric arrangement of reticulum saccules. The ultrastructural alterations were reversible only for S. virgata and E. speciosa. The seedlings of S. parahyba and S. commersoniana were more sensitive to oxygen deprivation and presented extensive cell disruption. The results are discussed in terms of energy supply.

Functional capacity, obesity and hypothalamic involvement: cross-sectional study on 212 patients with childhood craniopharyngioma.

The aim of this study was to analyze the impact of hypothalamic involvement of craniopharyngioma on functional capacity (FC) and obesity in 212 patients with childhood craniopharyngioma. FC could be evaluated using an ability scale (Fertigkeitenskala Münster-Heidelberg [FMH]) in 174 patients with childhood craniopharyngioma. Obesity was quantified in 212 patients at the time of diagnosis and at the time of latest evaluation by body mass index SDS [BMI]. The influence of hypothalamic tumor involvement on FC and BMI was analyzed. Patients with hypothalamic involvement (n = 125) presented with higher BMI SDS at the time of diagnosis (p = 0.001) and at latest follow-up evaluation (p < 0.001). FC as measured by FMH percentiles was lower (p < 0.001) in patients with hypothalamic involvement when compared with patients without hypothalamic involvement. FC negatively correlated (p < 0.001) with BMI SDS (Spearman's Rho = -0.40) only in patients with hypothalamic involvement whereas no correlation between FC and BMI SDS was found in patients without hypothalamic involvement. We conclude that hypothalamic involvement of childhood craniopharyngioma had major impact on FC in survivors. Obesity resulted in impaired FC of patients with hypothalamic involvement. BMI at diagnosis was a sensitive parameter to identify patients at risk of severe obesity. Further analysis on this issue is performed in the prospective, multicenter surveillance study on children and adolescents with craniopharyngioma (KRANIOPHARYNGEOM 2000).

Perioperative dexamethasone treatment in childhood craniopharyngioma--influence on short-term and long-term weight gain.

The substitution of dexamethasone during and after surgery of childhood craniopharyngioma is necessary in order to treat and/or prevent brain edema and adrenal insufficiency. Early post-operative weight gain is a predictor for severe obesity during long-term follow-up. In a retrospective analysis of 60 patients with childhood craniopharyngioma we inquired whether dose and duration of perioperative dexamethasone therapy (n = 68) had influence on short-term post-operative weight gain and long-term development of severe obesity. The median follow-up period was 4.2 years, ranging from 1 to 9 years. 24 patients (14 f/10 m) developed severe obesity (BMI > 3 SD). 28 patients (10 f/18 m) retained normal weight (BMI < 2 SD). Eight patients presented with a BMI between 2 and 3 SD at the final visit. Differences in terms of age at surgery or follow-up period were non-detectable between the analyzed groups of craniopharyngioma patients. Duration and cumulative dexamethasone doses (mg/m2 BSA) for perioperative dexamethasone therapy were similar for severely obese patients (duration: 8.7 d; 4.5 - 17 d, cumulative dose: 74; 42 - 177 mg/m2 BSA) and normal weight patients (duration: 10.0 d; 1 - 41 d; dose: 76; 9 - 390 mg/m2 BSA). Whereas cumulative dexamethasone doses positively (p < 0.01; rho: 0.424) correlated with weight gain during the first year following surgery, long-term development of severe obesity was not influenced by dose and duration of perioperative dexamethasone treatment. Patients who developed severe obesity during follow-up had a higher (p < 0.001) BMI already at the time of diagnosis. We conclude that dose and duration of perioperative dexamethasone treatment had short-term effects on post-operative weight gain, but not on the development of long-term severe obesity. The results of our retrospective analysis are currently tested in a prospective surveillance study Kraniopharyngeom 2000 (www.kraniopharyngeom.com).

Volumetric bone mineral density in patients with childhood craniopharyngioma.

As the overall survival rate is high in patients with craniopharyngioma, the prognosis in survivors depends mainly on late effects. Late effects such as hypogonadism, growth hormone deficiency, glucocorticoid overreplacement and obesity have a strong impact on volumetric bone mineral density (vBMD). We analyzed vBMD and possible risk factors for reduced vBMD in 61 patients with childhood craniopharyngioma (29 f; 32 m) and in 14 weight, age, and sex-matched controls. VBMD was quantified by peripheral quantitative computed tomography (pQCT). Endocrine status, hormonal substitution therapy and calcium phosphate metabolism were evaluated. VBMD was in the lower normal range in 61 craniopharyngioma patients (total radial z-scores: median - 1.5; range - 3.1 to 1.4; trabecular z-scores: median - 0.4; - 2.4 to 2.3). 23 severely obese patients (body mass index [BMI] > 4 SD) had a higher total radial (p < 0.05) and trabecular (p < 0.05) vBMD when compared with 38 non-severely obese patients and 7 weight-matched controls. Although there was no gender difference in terms of obesity, endocrine substitution therapy or calcium phosphate metabolism, male patients had lower total radial (p < 0.01) and trabecular (p < 0.05) vBMD. Only in male patients' vBMD z-scores showed a positive correlation with BMI standard deviation score (SDS) (total radial z-score: Spearman r = 0.38, p = 0.03; trabecular z-score: Spearman r = 0.35, p = 0.04). We conclude that obesity has a major impact on vBMD in patients with craniopharyngioma. Lean male patients are at special risk for a lower vBMD, whereas female gender and severe obesity seem to have a protective effect regarding vBMD.

Randomised trial: One cycle of anthracycline-containing adjuvant chemotherapy compared with six cycles of CMF treatment in node-positive, hormone receptor-negative breast cancer patients.

AIM: A randomised, controlled clinical trial was initiated in 1984 to test whether 1 cycle of anthracycline-containing adjuvant chemotherapy improves the outcome of breast cancer patients presenting with stage II disease and negative oestrogen and progesterone receptors (ER, PgR), as compared with 6 cycles of dose-reduced CMF. PATIENTS AND METHODS: Within 7 years 263 women with stage II breast cancer were randomised either to receive 1 cycle of doxorubicin, vinblastine, cyclophosphamide, methotrexate and 5- fluorouracil (AV-CMF) or to receive 6 cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Patients were stratified for tumour stage, nodal stage, menopausal status, type of surgery and participating centre. RESULTS: After a median follow-up of 100 months, neither disease-free (DFS) nor overall survival (OS) differed significantly between the two groups. CONCLUSIONS: Compared to 6 cycles of a non-standard low-dose CMF regimen 1 cycle of anthracycline- containing adjuvant chemotherapy failed to improve the outcome in women with stage II receptor-negative breast cancer in terms of DFS and OS.

Melanin offers protection against induction of cyclobutane pyrimidine dimers and 6-4 photoproducts by UVB in cultured human melanocytes.

The goal of this investigation was to correlate the melanin content in human pigmentary cells with the generation of UVB-induced photoproducts and to examine the relationship between the melanin content and the removal of the photoproducts. Cultured melanocytes from light-skinned individuals synthesized less melanin and produced more cyclobutane pyrimidine dimers and 6-4 photoproducts upon UVB exposure than did melanocytes from black skin. Tyrosine-stimulated melanogenesis provided protection against DNA damage in both cell types. In another set of pigmented cell lines a ratio between eumelanin and pheomelanin was determined. The assessment of association between DNA damage induction and the quantity and quality of melanin revealed that eumelanin concentration correlated better with DNA protection than pheomelanin. Skin type-I and skin type-VI melanocytes, congenital nevus (CN)-derived cells and skin type-II melanocytes from a multiple-melanoma patient were grown in media with low or high L-tyrosine concentration. The cells were irradiated with 200 J/m2 UVB, and the levels of the photoproducts were determined immediately and after 6 and 24 h. Once again the induction of the photoproducts was mitigated by increased melanogenesis, and it was inversely correlated with the skin type. No significant differences were found for the removal of photoproducts in the cultures of skin types I and VI and CN cells. No indications of a delay in the removal of photoproducts in the melanocytes from the multiple-melanoma patient were found either.

Variation in melanin content and composition in type V and VI photoexposed and photoprotected human skin: the dominant role of DHI.

A combination of techniques, including high-performance liquid chromatography (HPLC), spectrophotometric measurements, and a novel method for quantifying melanosome morphology, were applied to the analysis of melanin content and composition in highly pigmented (Fitzpatrick type V and VI) human skin. We found that total epidermal melanin content is significantly elevated in photoexposed type V and VI skin (approximately 1.6 x), while analysis of individual melanin components suggests that pheomelanin content increases only slightly, whereas 5,6-dihydroxyindole-2-carboxylic acid (DHICA)-eumelanin and to a greater extent 5,6-dihydroxyindole (DHI)-eumelanin content are both markedly elevated. Analysis of the relative composition of epidermal melanin in these subjects revealed that DHI-eumelanin is the largest single component (approximately 60-70%), followed by DHICA-eumelanin (25-35%), with pheomelanin being a relatively minor component (2-8%). Moreover, there was a comparative enrichment of DHI-eumelanin at photoexposed sites, with a corresponding decline in the relative contributions from DHICA-eumelanin and pheomelanin. There was also a good correlation and close agreement between the concentration of spheroidal melanosomes determined by morphological image analysis and the concentration of pheomelanin determined by a combination of HPLC and spectrophotometric analysis (r = 0.89, P < 0.02). This study demonstrates the usefulness of melanosome morphology analysis as a sensitive new method for the quantification of melanin composition in human skin. The data also suggest that DHI-eumelanin formation is the dominant pathway for melanin synthesis in heavily pigmented (Fitzpatrick V and VI) skin types in vivo, and is the favoured pathway when melanin production is increased in chronically photoexposed skin.

[Bone manifestations in non-Hodgkin's lymphoma in childhood and adolescence]. / Ossäre Manifestationen beim Non-Hodgkin-Lymphom im Kindes- und Jugendalter.

PURPOSE: Skeletal manifestation of Non-Hodgkin's lymphoma is rare in pediatric patients. Objective of the study was to determine imaging features, before and after treatment, and to correlate these features with clinical outcome. METHODS: A retrospective analysis of 1246 patients from two therapy studies (NHL-BMF-90 and 95) was performed. Imaging studies of 63 patients with bone involvement of lymphoma were reevaluated. RESULTS: Incidence of initial bone involvement in Non-Hodgkin's lymphoma was 6.8%. Distribution was best assessed by bone scan, MRI revealed larger areas of marrow involvement and detected additional lesions. Sites of predilection were long bones of the lower extremities with epiphyseal involvement in 39%. Residual signal alterations in MRI after successful therapy remained in 71%. Osteonecrosis after therapy was a common finding. Clinical outcome war not correlated to the presence of bone involvement. CONCLUSIONS: Since clinical outcome is not effected by bone involvement in childhood NHL, value of screening may be limited. Knowledge of imaging characteristics is mandatory for initial evaluation of primary osseous lymphomas and symptomatic lesions as well as for therapy controls.