[Evaluation of the microcirculation in critically ill patients : Relevance, practical possibilities and scientific evidence]. / Evaluation der Mikrozirkulation bei kritisch kranken Patienten : Relevanz, praktische Möglichkeiten und wissenschaftliche Evidenz.

As one critical parameter for organ perfusion, microcirculation and its monitoring are gaining increasing attention for modern intensive care medicine. The growing understanding of its importance in organ failure and the improved modes of its visualization mark microcirculation as an interesting target. Surrogate parameters for organ perfusion, like re-capillarization ("Recap") time, the "mottling score" or the measurement of serum lactate have long been established in clinical practice. A growing body of evidence is hinting towards online visualization of sublingual microcirculation using intravital video microscopy, which was shown to be of prognostic value. Furthermore, the measurement of objective and reproducible parameters hint towards use in individualized hemodynamic therapy.

Development of curative therapies for Ewing sarcomas by interdisciplinary cooperative groups in Europe.

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.

Testicular germ cell tumors in adolescents - results of the protocol MAHO 98 and the identification of good risk patients.

BACKGROUND: In adolescents aged 10-15 years germ cell tumors of the testis (TGCT) are rare and information for a risk adapted therapy limited. AIMS OF THE STUDY: The protocol MAHO 98 for patients (pts) with TGCTs is stratified according to age, stage and histology. Pts ≥ 10 years received after tumororchiectomy 2 courses (crs) PVB and restaging. Residual tumor was resected and therapy continued in regard to inital stage and response. Chemotherapy: PVB: cisplatin (20 mg/m²/day 1-5), vinblastine (3 mg/m²/day 1+2), and bleomycin (15 U/m²/day 1-3). For consolidation 1 crs PVB has been given to stage II patients with CR. In case of PR, 2 crs PEB (vinblastine substituted by etoposide 100 mg/m²/day 1-3) or relapse 3 crs PEI (bleomycin substituted by ifosfamide 1 500 mg/m²/day 1-5) were given. RESULTS: Between Jan 1998 and Dec 2005, 34 pts (≥ 10 year) were registered, 31 fulfilled the inclusion criteria. Median age: 15;6 years; months (range 13;5-20;2 ). Lugano staging: IA n=14, IB n=2, IC n=3, IIA n=4, IIB n=6, IIC n=1, IIIC n=1. The stage IIIC pt received preoperative chemotherapy, all other pts had tumororchiectomy first. Residual tumor after 2 crs PVB was detected in 4 pts and was resected. Late relapses occurred in 2 pts and were cured by additional therapy. All patients are surviving. CONCLUSION: Young patients with TGCT stage I and II have an excellent prognosis and further reduction of therapy has to be considered.

Significantly increased CD70 up regulation on TEL-AML positive B cell precursor acute lymphoblastic leukemia cells following CD40 stimulation.

BACKGROUND: TEL-AML the most common genetic alteration in childhood precursor B acute lymphoblastic leukemia (BCP-ALL) is associated with a favorable prognosis. PATIENTS AND METHOD: We studied the expression of nerve growth factor/tumor necrosis factor receptor (NGFR/TNFR)/ligand family members on 108 primary BCP-ALL samples by flow cytometry and compared both their baseline expression and CD40-induced modulation on TEL-AML positive and negative leukemia samples. RESULTS: Our findings demonstrate that TEL-AML positive patients exhibit a significantly higher percentage of CD40, CD27 and p75NTR positive blasts at diagnosis. This might well contribute to the improved relapse-free survival of these patients assessed in Kaplan Meier analysis as CD27 and p75NTR directly mediate apoptotic signals. Furthermore CD40 ligation enhances antigen presenting and T cell stimulatory capacity via significant up regulation of CD70 while adequate response to physiological maturation signals as indicated by concomitant down regulation of CD27 is retained in TEL-AML positive leukemia. CONCLUSION: These data provide novel insights in immunological control mechanisms preserved in this leukemia subtype and suggest that not only treatment with chemicals such as HDAC inhibitors but also retained in vivo response to CD40 ligation contributes to improved immune surveillance in these patients which may add to a superior relapse-free survival observed particularly in the presence of other risk factors.

Testicular sex cord stromal tumors: analysis of patients from the MAKEI study.

BACKGROUND: In children and adolescents, testicular sex cord stromal tumors (TSCSTs) are rare. There is only limited information available regarding their clinical presentation, biology, and prognosis. METHODS: Between 1993 and 2009, 42 patients were prospectively reported to the cooperative MAHO and MAKEI studies on childhood germ cell tumors. Based on standardized documentation, data on epidemiology, clinical presentation, diagnostic features, histopathological differentiation, therapy, and follow-up were evaluated. RESULTS: During the study period, a gradual increase of the documentation of these rare tumors was observed. Palpable, indolent testicular swelling was the most common clinical finding. In three patients, retention of the testis was observed. Two patients showed sexual precocity, and one patient showed a 45X/46XY mosaic. Juvenile granulosa cell tumors (n = 16) and Sertoli cell tumor (n = 15) were the leading histopathological subtypes. The first were commonly diagnosed during the first weeks of life (median age: 6(0-162) days, the latter during infancy (median 7(0-14) months, P < 0.05). Other histological diagnoses included Leydig cell and Large Cell Calcifying Sertoli cell tumors (both n = 3) and not-otherwise-specified TSCSTs (n = 5), which were diagnosed during childhood and adolescence. All tumors were limited to the testis; there were no metastases. Treatment was surgical, only. After a median follow-up of 3.8 years, no relapse was observed. CONCLUSIONS: Diagnosis and therapy of testicular tumors should be planned in accordance with the recommendations of the respective childhood germ cell tumor protocols. High inguinal orchiectomy is safe and constitutes definitive therapy. Diagnostic work-up and follow-up should also consider potentially associated tumor predisposition syndromes.

Testicular germ cell tumors in boys <10 years: results of the protocol MAHO 98 in respect to surgery and watch & wait strategy.

UNLABELLED: In 1982 the GPOH opened the 1st protocol for germ cell tumors (GCTs) of the testis (MAHO 82). Here the results of the 5th version (MAHO 98) will be offered for boys <10 year of age.In MAHO 98 watch and wait (w&w) strategy after inguinal tumororchiectomy was widened from 2 to 10-year-old boys with YST stage IA (group I); other invasive measures were omitted. Thus the prognostic impact of a non-recommended surgery like transscrotal operation +/- conventional biopsy (group II) can be evaluated.Clinical diagnosis and staging by ultrasound and tumor marker. In blurry cases, a frozen section was recommended to confirm the diagnosis by histology intraoperatively. Indications for adjuvant chemotherapy were: YST stage IA without elevated AFP, YST stage>IA and all mixed malignant GCTs.From 1998 till 2005 128 boys <10 years with a testicular GCT were registered. HISTOLOGY: YST n=76, teratoma n=46, mixed malignant GCT n=6. Tumor stage IA: n=101. All teratoma patients survive event-free. At all, only 19/82 patients with a malignant GCT received chemotherapy including 5 patients with a tumor progress after w&w (2/49 group I and 3/15 group II patients, respectively) and 1 patient (YST IIIA) with relapse after adjuvant chemotherapy. Transscrotal surgery (n=18) or tumorenucleation (n=6) remained without event. Indeed all patients survived.Prognosis of boys <10 year with a testicular GCT is excellent as ~80% will be cured by high inguinal tumororchiectomy alone. w&w is feasible and safe even after not recommended surgery if suitable follow-up is assured at least in stage IA cases.

[Rating and ranking of medical journals: a randomised controlled evaluation of impact factor and number of listed journals]. / Rating und Ranking medizinischer Zeitschriften: Randomisiert kontrollierte Evaluation von Impact Factor und Zahl der gelisteten Journale.

BACKGROUND: The impact factor is a purely bibliometric parameter built on a number of publications and their citations that occur within clearly defined periods. Appropriate interpretation of the impact factor is important as it is also used worldwide for the evaluation of research performance. RESEARCH QUESTION: It is assumed that the number of medical journals reflects the extent of diseases and patient populations involved and that the number is correlated with the level of the impact factor. METHOD: 174 category lists (Subject Categories) are included in the area Health Sciences of the ISI Web of Knowledge of Thomson Reuters, 71 of which belong to the field of medicine and 50 of which have a clinical and/or application-oriented focus. These alphabetically arranged 50 category lists were consecutively numbered, randomized by odd and even numbers, respectively, into 2 equal-sized groups and then grouped according to organ specialities, sub-specialities and cross-disciplinary fields. By tossing up a coin it was decided which group should be evaluated first. Only then the category lists were downloaded and the number of journals, as well as the impact factors of journals ranking number 1 and 2, as well as the impact factors of journals at the end of the first third and at the end of the first half of each category list were compared. RESULTS: The number of journals per category list varies considerably between 5 and 252. The lists of organ specialties and cross-disciplinary fields include more than three times as many journals as those of the sub-specialities; the highest numbers of journals are listed for the cross-disciplinary fields. The level of impact factor of journals that rank number 1 in the lists varies considerably and ranges from 3,058 to 94,333; a similar variability exists for the journals at rank 2. On the other hand, the impact factor of journals at the end of the first third of the lists varies from 1,214 and 3,953, and for those journals at the end of the first half of a respective category list it varies from 0,609 and 2,872. The slope of the straight correlation line between the level of impact factors of journals at rank 1 and 2 with the number of listed journals varies from 0,0756 and 0,2651 (correlation coefficients between 0,49 and 0,96). For the journals ranking further down in the lists the straight correlation lines run almost horizontally or with inverse slope. CONCLUSIONS: This current analysis adds to the knowledge for an appropriate interpretation of the impact factor. Generally, greater importance should be given to the ranking of a journal within a corresponding category list.

Molecular genetic analysis of bilateral ovarian germ cell tumors.

BACKGROUND: Ovarian germ cell tumors (oGCTs) are rare and highly heterogeneous with regard to their clinical and histologic appearance. The risk of tumor development is higher in children with aberrant sexual differentiation. Development of gonadoblastomas is seen in young women with 46,XY gonadal dysgenesis. At least 50 % of gonadoblastomas may develop into malignant oGCTs, mostly dysgerminomas. In this study, we evaluated bilateral oGCTs in clinically inapparent patients for sex chromosomal aberrations. PATIENTS AND METHODS: We analyzed tumor samples of 15 patients with synchronous bilateral oGCTs enrolled onto the consecutive MAKEI trials for non-testicular GCTs. Paraffin embedded samples from the Kiel German Childhood Tumor Registry were evaluated for the presence of Y-chromosomal sequences. Molecular genetic techniques included comparative genomic hybridization, polymerase chain reaction, and fluorescence in situ hybridization. RESULTS: Among 15 patients with bilateral oGCTs, Y-chromosomal DNA sequences were detected in 6 tumors. Both mature teratomas were negative for Y-chromosomal DNA. Thus, 5 of 12 malignant oGCTs and 1 immature teratoma (with elevated AFP) showed Y-chromosomal material. A 45(X,0) karyotype could not be demonstrated. CONCLUSIONS: These investigations provide additional insight into the development of oGCTs: mature teratomas, which develop from postmeiotic germ cells, are not associated with gonadal dysgenesis. Bilateral immature teratomas, dysgerminomas and mixed malignant oGCTs may frequently show Y-chromosomal DNA, indicating underlying but clinically inapparent gonadal dysgenesis. Thus, the presence of aberrant Y-chromosomal sequences appears to be involved in tumor development in about half of these patients.

MHC class II deficiency cured by unrelated mismatched umbilical cord blood transplantation: case report and review of 68 cases in the literature.

MHC class II deficiency is a rare and fatal form of primary combined immunodeficiency caused by a lack of T-cell-dependent humoral and cellular immune response to foreign antigens, which can only be cured by allogenic stem cell transplantation. In the literature search, we identified 68 cases of HSCT in MHC class II deficiency in the last 14 yr. Pre- and post-transplant MHC class II deficiency is complicated by overwhelming viral infections, a high incidence of GvHD, and graft failure with a poor overall survival rate below 50%. We report an eight-month-old boy presenting with severe respiratory infections and chronic diarrhea, whose sister died at the age of four yr from septicemia. MHC II deficiency was caused by an RFXANK-mutation and treated successfully by 4/6 mismatched unrelated CBT after a myeloablative conditioning regimen based on anti-thymocyte globulin, busulfane, fludarabine, and cyclophosphamide. At present, our patient is well with full immune reconstitution 3(4/12) yr after CBT. CB may represent an alternative source of stem cells for children with MHC class II deficiency without a suitable donor.

Cis-regulatory evolution spotlights species differences in the adaptive potential of gene expression plasticity.

Phenotypic plasticity is the variation in phenotype that a single genotype can produce in different environments and, as such, is an important component of individual fitness. However, whether the effect of new mutations, and hence evolution, depends on the direction of plasticity remains controversial. Here, we identify the cis-acting modifications that have reshaped gene expression in response to dehydration stress in three Arabidopsis species. Our study shows that the direction of effects of most cis-regulatory variants differentiating the response between A. thaliana and the sister species A. lyrata and A. halleri depends on the direction of pre-existing plasticity in gene expression. A comparison of the rate of cis-acting variant accumulation in each lineage indicates that the selective forces driving adaptive evolution in gene expression favors regulatory changes that magnify the stress response in A. lyrata. The evolutionary constraints measured on the amino-acid sequence of these genes support this interpretation. In contrast, regulatory changes that mitigate the plastic response to stress evolved more frequently in A. halleri. Our results demonstrate that pre-existing plasticity may be a stepping stone for adaptation, but its selective remodeling differs between lineages.

Brain metastases in children and adolescents with extracranial germ cell tumor - data of the MAHO/MAKEI-registry.

BACKGROUND: We analyzed 15 children and adolescents with extracranial germ cell tumor (GCT) and brain metastases reported to the MAHO/MAKEI registry. PATIENTS AND METHODS: Between 1982 and 2009, 2 077 patients were prospectively enrolled onto the MAHO/MAKEI studies (overall survival: 0.88+/-0.03). All patients with advanced malignant GCTs received cisplatin-based chemotherapy (overall survival: 0.81+/-0.04 (734/823). RESULTS: 15 patients with brain metastases were reported; in 6 of them at diagnosis and 9 respectively during follow-up (6 weeks-28 months after end of therapy, mean=10 months). Most patients were male (13/15) and adolescent (10/15). 8 patients suffered from mediastinal GCTs. Pure Choriocarcinoma (CC) or CC in combination with other histologies was diagnosed in 12 patients. Clinical symptoms were reported in most patients. In all patients with secondary brain metastases the previously normalised tumor markers AFP and/ or HCG increased again prior to the onset of neurological symptoms. Only 1 of the patients with primary brain metastases survived, whereas 4 of 9 with secondary metastases are in remission after additional treatment. CONCLUSION: The risk for intracranial metastases increases with age, male gender and mediastinal or testicular primary site and choriocarcinoma histology. Development of neurological symptoms at initial diagnosis or during follow-up should lead to rapid clinical re-evaluation including CNS imaging and assessment of tumor markers. Treatment of brain metastases includes intensified chemotherapy and surgical resection, irradiation has to be considered in special clinical situations.

Proton beam therapy for loco-regional control of a recurrent mixed malignant germ cell tumor of the skull in a 22-month-old girl.

BACKGROUND: Germ cell tumors (GCT) situated in the head and neck region are very rare and occur predominantely in newborns or young infants. Recurrent CTs are often resectable only by mutilating surgery and the need for alternative treatment strategies is obvious. In this situation radiation therapy is the most important treatment option for loco-regional tumor control, but bear in this area the risk of possible impairment of brain function and face deformation as long term effects. CASE REPORT: In a girl with a connatal expansive growing teratoma of the skull the tumor recurred in spite of repeated surgery as mixed malignant GCT at the age of 15 months. Tumor control could not be achieved with chemotherapy and additional surgery seemed not promising. Therefore high dose proton beam therapy (PT) (54 Gy) has been administered to the child at the age of 22 months and led to local tumor control with only mild side effects. CONCLUSION: PT treatment may be an option for specific clinical conditions in germ cell tumors where local tumor control cannot be achieved by chemotherapy and/or surgery and long lasting side effects of conventional radiotherapy due to tumor localization and age have to be considered. However, PT should be implemented in treatment protocols for specific situations to guarantee supervised application, central documentation and follow-up.

[Process and outcome quality of the German Paediatric Surveillance Unit (ESPED)]. / Evaluation der Prozess- und Ergebnisqualität der Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland (ESPED).

UNLABELLED: The German paediatric surveillance unit (ESPED) was founded in 1992 with the objective to generate incidence data and to describe symptoms, diagnostic procedures, therapy and prevention for rare paediatric diseases requiring in hospital treatment. Every month the ESPED office sends a mailing card to the heads of all paediatric departments asking for the incident diagnosis of up to 12 conditions. In 2007 about 96% of the cards are returned. Each condition is represented by a principal investigator. Up till now surveillance of 52 conditions has been performed. Reports on the mailing card prompt immediate mailing of the full questionnaire. For 43 conditions the return rates were in the range of 70-100% and for 7 conditions <70% (unknown 2). The highest return rates were achieved if the principal investigator was supported by staff comprising at least two persons or if the mailing of the questionnaire was handled by the ESPED office. The scientific impact of the ESPED System was assessed by the impact factors of the journals, in which the respective ESPED studies were published. By August 31 (st) 2008 the investigators of 38 studies reported up to 7 publications per conditions surveyed. A total of 104 publications was reported: 27 of these appeared in journals without an impact factor. Among the 77 other publications 10 appeared in journals with an impact factor >10. CONCLUSION: Surveillance in ESPED has contributed significantly to high quality research on rare conditions in children.

Telemicroscopic conferences for children of the Perm territory with suspected or proven malignant solid tumors.

BACKGROUND: Malignant solid tumors are rare events in childhood and adolescence. Therefore central review of the histology and standardized grading are requested for accurate risk estimation and facilitate a tumor risk adapted treatment. AIMS OF THE STUDY: To abandon the time consuming transportation of tumor material over long distances to the specialized institution by implementation of an internet based consultation system. METHODS: A microscope combined with a videocamera (situated in Perm) and the personal computers of each of 4 cooperating institutions (in Perm, Kiel, Koeln, Duesseldorf) has been equipped with the special software Mikroskopkonferenz. Additional videocameras allow the transmission of the cooperators to each other. Headsets are used to avoid reecho. As a prerequisite an internet connection with a 54 KBits capacity has to be provided. RESULTS: Between January and December 2009, 26 children (median age 2; 5 years, 12 females and 14 males) with suspected or proven malignant solid tumors have been discussed in 11 telemicroscopic conferences by international cooperators. CONCLUSION: This cooperation demonstrates the proof of principle to obtain second opinions in short time over far distances for seldom diseases on a scientific level.

Filamentous structures in adherent Mycoplasma pneumoniae cells treated with nonionic detergents.

Mycoplasma pneumoniae cells adhering to glass or Parlodion-coated grids were extracted with Triton X-100. The extracted cells showed a cytoskeleton consisting of a rodlike tip structure and a filamentous network in the cytoplasm. The tip structure was up to 300 nm long and approximately 40 nm wide ending at the distal end in a bleb-like structure, and seemed to consist of filaments arranged in parallel, 4.8 +/- 0.5 nm wide. In the cytoplasm the filaments formed an irregular lattice. Similar filaments were found in platinum replicated critical-point dried extracted cells. An actinlike nature of the filaments is suggested by some of their properties, but the degree of homology with respect to eucaryotic actin is still unknown. The filaments were sensitive to protease treatment but stable in high molar KCl solutions. They were apparently destroyed by incubation in high molar KI solution, leaving only some parts of the tip structure. Formaldehyde-fixed M. pneumoniae cells treated with Triton X-100 bound rhodamine-labeled phalloidin specifically. Furthermore, they could be stained with antiactin antibodies. Binding of myosin subfragment 1 to the filaments was not observed.

Cloned mycoplasma ribosomal RNA genes for the detection of mycoplasma contamination in tissue cultures.

A cloned fragment of the mycoplasma ribosomal RNA operon was used as a molecular probe for the detection of mycoplasmas in cell cultures. According to the conditions of hybridization, the probe can detect prokaryotes in general or mycoplasmas specifically.

Present risk of anthracycline or radiation-induced cardiac sequelae following therapy of malignancies in children and adolescents.

Anthracyclines are very potent drugs in the therapy of malignancies in childhood. The major dose limiting adverse effect of these drugs is the risk of dilated cardiomyopathy. We performed a retrospective study on 168 patients who were treated with anthracyclines for a malignant disease with or without chest radiation at the department of Pediatric Hematology and Oncology at the University of Duesseldorf between 2000 and 2004. During and after chemotherapy the patients were screened by echocardiography and ECG examinations prior to each administration of anthracyclines. Only four patients presented with adverse cardiac events, one of whom developed acute cardiac failure. This patient was additionally treated with chest radiation. Three of the four patients showed intermittent arrhythmias, mainly supraventricular tachycardia. One of them presented with atrial ectopic tachycardia and left ventricular dysfunction. We conclude that the frequency of cardiac sequelae after chemotherapy with anthracyclines is low under present guidelines. Detection of early cardiac sequelae may be more difficult than in the past. Only one patient with cardiac sequelae in our study group was diagnosed by regular performed examinations for cardiac sequelae of chemotherapy. We therefore need to modify our screening methods to increase the effectiveness of detection of cardiac dysfunction prior to clinical manifestation.

Symptoms of childhood acute lymphoblastic leukemia: red flags to recognize leukemia in daily practice.

BACKGROUND: The aim of this study is to identify clinical "red flags" that may assist the general pediatrician in detecting patients with an acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Medical history and clinical findings of 189 children and adolescents, diagnosed with ALL between 1/1995 and 7/2004, were analyzed retrospectively. RESULTS: Only 50% of patients presented with symptoms known in children with leukemia (fever, fatigue, paleness, hemorrhage); 5% were diagnosed accidentally in the absence of any clinical symptoms. The majority of patients had a medical history up to few weeks; in 11% of patients up to several months without impairing curability. 95% of the patients presented at diagnosis with enlargement of lymphnodes, liver and/or spleen. The characteristic laboratory constellation included mono-, respectively bi- or trilinear pathology of the blood count and with blasts in the blood smear. CONCLUSION: The clinical diagnosis of ALL relies on physical examination and the blood count including microscopic examination. Therefore, the alertness of the treating paediatrician with regard to clinical findings and a pathologic blood count is more important than elaborate laboratory investigations. In uncertain cases, a close follow-up examination may help to unmask ALL, which will most likely be stratified in the low-risk-group.

Survival after an antiangiogenetic therapy and surgery in a wide spread growing teratoma originating from a testicular mixed malignant germ cell tumor.

Growing teratoma is still an often unsolved problem especially in male with mixed malignant GCTs of the testis or the mediastinum. This specific situation with progressive tumor growth and simultaneous normalization of tumor markers during or after treatment of malignant GCTs with teratomatous elements is judged as a fatal situation if this situation can not be controlled by extensive surgery, as teratoma are not sensible to chemotherapy or irradiation. Here, we report the case history of a 17-year old male patient with a testicular malignant GCT and wide spread lymph node metastases, who developed a rapidly progressive growing teratoma within the lymph node metastases. Within the molecular profile of the tumor we could find a cytogenetic picture typically found in malignant adult GCTs. In view of the bulky abdominal, thoracic and cervical metastases and the uncontrolled tumor progression, the situation was considered incurable. However, following an individual treatment attempt, this patient was treated with a four-agent combination of drugs with antiangiogenetic potential as well as low-dose cyclic chemotherapy. This approach resulted in a sustained disease stabilization followed by extensive surgical resection of the metastases. We therefore would like to highlight this treatment approach in unresectable growing teratoma and would like to stimulate further research and collaboration to come to an optimized treatment suggestion for this group of poor prognostic patients.