[Recommendations for quality standards in bronchoscopy].
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Evidence-Based Medicine↗
Biomedical subjects
W Hartmann
Publications and source records attributed to W Hartmann.
Vinorelbine alternating oral and intravenous plus carboplatin in advanced non-small-cell lung cancer: results of a multicentre phase II study.
BACKGROUND: Vinorelbine and carboplatin are both active agents in the treatment of non-small-cell lung cancer (NSCLC). Vinorelbine has recently been developed in an oral formulation, which is as active as the intravenous (i.v.) form. PATIENTS AND METHODS: Fifty-two chemonaive patients with unresectable localised or metastatic NSCLC received i.v. vinorelbine 25 mg/m(2) plus carboplatin (AUC 5) on day 1 and oral vinorelbine 60 mg/m(2) on day 8 (or day 15 if neutrophils <1500/mm(3)) every 3 weeks in an open-label, multicentre phase II study. RESULTS: A total of 224 cycles were given, with the median number per patient of four (range one to eight). Eight responses out of 52 enrolled patients were documented and validated by an independent panel review, yielding a response rate of 18.2% [95% confidence interval (CI) 6.8-29.6%] in the evaluable population. This response rate was balanced by a high rate of disease control (78.9% in the intention-to treat population and 90.9% in the evaluable population). The median progression-free and median survival were 5.1 months (95% CI 4.3-8.1) and 9.3 months (95% CI 6.8-11.4), respectively. Overall, the safety profile of the combination regimen alternating i.v. and oral vinorelbine appeared similar to that expected for each individual agent. Some lung cancer-specific items (pain, dyspnoea) improved or were stabilised by assessment using the EORTC QLQ-C30 and QLQ-LC13 questionnaires. CONCLUSIONS: The combination of carboplatin with an alternating regimen of i.v./oral vinorelbine is a well tolerated regimen with a low level of toxicity and a low rate of serious adverse events. A high rate of disease control (partial response + no change) was achieved. Progression-free survival and overall survival fell within the expected range. This regimen is convenient and safe for the treatment of patients with locally advanced or metastatic NSCLC patients.
Administration, Oral↗
No evidence for mutations or altered expression of the Suppressor of Fused gene (SUFU) in primitive neuroectodermal tumours.
The sonic hedgehog (Shh) and the Wnt signalling pathways are involved in the development of medulloblastomas (MBs), the most frequent malignant brain tumours in children. Components of these two developmental and cancer-associated pathways, including (Patched) PTCH, SMOH, adenomatous polyposis coli (APC), beta-catenin and AXIN1 show somatic mutations in sporadic MBs. In this study we analysed SUFU (human Suppressor of Fused), which acts as a negative regulator of both the Shh and Wnt signalling pathways and therefore represents a putative tumour suppressor gene, to find out if it is also involved in the pathogenesis of sporadic MBs. We screened 145 primitive neuroectodermal tumours (PNETs) including 90 classic MBs, 42 of the desmoplastic variant and two medullomyoblastomas as well as 11 MB cell lines for mutations using single-strand conformational polymorphism (SSCP) and sequencing analysis. 18% of the MBs exhibited allelic losses on chromosome 10q. In contrast to a previous report, in which truncating mutations of SUFU have been identified in 9% of MBs, we were not able to identify somatic mutations of SUFU in our large tumour panel. We uncovered single nucleotide polymorphisms (SNPs) in exon 4, 8, 11 and in intron 2 in the SUFU gene. Expression analysis by competitive reverse transcription-polymerase chain reaction (RT-PCR) revealed no difference in SUFU mRNA levels of both MB subtypes and normal foetal or adult cerebellar tissues. Our results indicate that genetic alterations of the SUFU gene, do not contribute significantly to the molecular pathogenesis of MBs.
Adolescent↗
Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors.
Primitive neuroectodermal tumors (PNETs) represent the most frequent malignant brain tumors in childhood. The majority of these neoplasms occur in the cerebellum and are classified as medulloblastomas (MB). Most PNETs develop sporadically; however, their incidence is highly elevated in patients carrying germline APC gene mutations. The APC gene encodes a central component of the WNT/wingless developmental signaling pathway. It regulates the levels of cytoplasmic beta-catenin protein that plays a central role in neural development and cell proliferation. We analyzed 87 sporadic PNETs and 10 PNET cell lines for mutations of the APC gene and beta-catenin (CTNNB1) gene using single strand conformational polymorphism (SSCP) and sequencing analysis. We examined the mutation cluster region of APC (codons 1255--1641) for germline variants and somatic mutations. The medulloblastoma cell line MHH-MED-2 carried a Glu1317Gln missense germline variant and a sporadic MB sample showed a somatic Pro1319Leu substitution. Mutational analysis of exon 3 of CTNNB1 uncovered 4 PNETs (4.8%) with somatic missense mutations. These mutations caused amino acid substitutions in 3 of 80 medulloblastomas (Ser33Phe, Ser33Cys and Ser37Cys) and 1 of 4 supratentorial PNETs (Gly34Val). All mutations affected GSK-3 beta phosphorylation sites of the degradation targeting box of beta-catenin and resulted in nuclear beta-catenin protein accumulation. Deletions of CTNNB1 were not detected by PCR amplification with primers spanning exons 1--5. Our data indicate that inappropriate activation of the WNT/wingless signaling pathway by mutations of its components may contribute to the pathogenesis of a subset of PNETs.
Adenomatous Polyposis Coli Protein↗
Promoter-specific transcription of the IGF2 gene: a novel rapid, non-radioactive and highly sensitive protocol for mRNA analysis.
The human insulin-like growth factor-II (IGF2) is a regulatory peptide which is critical in normal fetal growth. IGF2 gene transcription is controlled by the usage of four promoters P1-P4 of which promoters P2-P4 are genomically imprinted. Disruption of imprinting and the resulting increase of gene dosage have been shown to be implicated in tumor progression in a variety of human tumors. Due to the need for high amounts of tissue material for conventional methods such as Northern blotting or ribonuclease protection assay (RPA), studies on IGF2 expression have most often been limited to the detection of total IGF2 transcript, though different dysregulatory events can be responsible for the abundance of IGF2 mRNA found in many tumors. We established a highly sensitive competitive RT-PCR assay for the four different transcripts of the IGF2 gene with transcript-specific external RNA competitors in which we take advantage of fluorescence-based quantification on a semiautomated sequencer. The amount of total RNA needed is approximately 100 times lower than the amounts required for Northern blotting or RPA, so that even cytological samples can be analyzed. We applied the assay to a series of eleven hepatoblastomas (HB) in which normal adjacent liver tissue could also be analyzed.
Child, Preschool↗
A multicenter randomized phase II study of oral vs. intravenous vinorelbine in advanced non-small-cell lung cancer patients.
PURPOSE: A randomized phase II trial of oral vs. intravenous (i.v.) vinorelbine was designed to determine the efficacy and safety of oral vinorelbine with an intrapatient dose escalation in previously untreated patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between December 1997 and April 1999, 115 patients with stage IIIB or IV NSCLC were randomized (2 to 1) to receive either oral vinorelbine at a dose of 60 mg/m2/week for the first three administrations and then increased to 80 mg/m2/week in the absence of severe neutropenia, or i.v. vinorelbine at 30 mg/m2/week. RESULTS: One hundred and fourteen patients (76 in the oral arm and 38 in the i.v. arm) were treated. Ninety-eight patients (86%) were eligible and assessable. The two treatment arms were well-balanced for demographic and prognostic features. After external panel review, the response rates in evaluable patients were 14%, in the oral arm and 12% in the i.v. arm. The median progression-free survival with oral and i.v. vinorelbine was 3.2 months and 2.1 months, respectively, and the median survival 9.3 and 7.9 months, respectively. The most common hematological toxicity was neutropenia, which was severe (grade 3-4) in 46% of patients and for 7% of administrations in the oral arm, and in 62% of patients and for 25% of administrations in the i.v. arm. Non-hematological toxicities including nausea, vomiting, anorexia, weight loss, diarrhea .and constipation were generally mild to moderate. CONCLUSION: The activity of oral and i.v. vinorelbine in advanced NSCLC appears to be comparable. The safety profiles of both formulations look qualitatively similar. Oral vinorelbine can therefore be considered a good alternative to i.v. administration.
Administration, Oral↗
Spectrum analysis of respiratory sounds in exercising horses with experimentally induced laryngeal hemiplegia or dorsal displacement of the soft palate.
OBJECTIVE: To record respiratory sounds in exercising horses and determine whether spectrum analysis could be use to identify sounds specific for laryngeal hemiplegia (LH) and dorsal displacement of the soft palate (DDSP). ANIMALS: 5 Standardbred horses. PROCEDURE: Respiratory sounds were recorded and pharyngeal pressure and stride frequency were measured while horses exercised at speeds corresponding to maximum heart rate, before and after induction of LH and DDSP. RESULTS: When airway function was normal, expiratory sounds predominated and lasted throughout exhalation. After induction of LH, expiratory sounds were unaffected; however, all horses produced inspiratory sounds characterized by 3 frequency bands centered at approximately 0.3, 1.6, and 3.8 kHz. After induction of DDSP, inspiratory sounds were unaffected, but a broad-frequency expiratory sound, characterized by rapid periodicity (rattling) was heard throughout expiration. This sound was not consistently detected in all horses. CONCLUSIONS AND CLINICAL RELEVANCE: The technique used to record respiratory sounds was well tolerated by the horses, easy, and inexpensive. Spectrum analysis of respiratory sounds from exercising horses after experimental induction of LH or DDSP revealed unique sound patterns. If other conditions causing airway obstruction are also associated with unique sound patterns, spectrum analysis of respiratory sounds may prove to be useful in the diagnosis of airway abnormalities in horses.
Animals↗
IGF-II and IL-2 act synergistically to alter HDAC1 expression following treatments with trichostatin a.
Histone deacetylases play key roles in the regulation of gene transcription. Studies have shown that expression of interleukins IL-2 and IL-8, and insulin-like growth factor 2 (IGF2) are affected by treatment with histone deacetylase inhibitors. We have previously shown that the gene for histone deacetylase 1 (HDAC1) is upregulated following treatment with TSA. The murine homologue of this gene has been reported to be inducible by IL-2. In this study, we have examined the effects IL-2, IGF-II and TSA have on HDAC1 expression in the human hepatocellular carcinoma derived cell line Hep3B. Our results indicate that in contrast to the mouse, HDAC1 is not inducible by IL-2. However, in TSA treated cells, IL-2 and IGF-II were found to act synergistically to reduce TSA induced HDAC1 mRNA levels almost to normal.
Acetylation↗
p57(KIP2) is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57(KIP2), IGF2, and H19.
Hepatoblastomas (HBs), representing malignant liver tumors of childhood, show frequent loss of heterozygosity (LOH) in the chromosomal region 11p15.5. This loss is of maternal origin suggesting the presence of a monoallelically expressed tumor suppressor gene in this region. p57(KIP2) (KIP2) located at 11p15.5 is predominantly expressed from the maternal allele and encodes a cyclin-dependent kinase inhibitor. We screened a series of 56 HB tumors and five HB cell lines for allelic loss (LOH) of the KIP2 locus by microsatellite analysis and KIP2 coding sequence mutations by single-strand conformation polymorphism analysis. Although LOH at the KIP2 locus occurred in 25% of the cases, no mutations were found. Analysis of KIP2 mRNA expression by competitive reverse transcriptase-polymerase chain reaction revealed up-regulation in nine of 12 HBs compared to matching liver samples. In contrast, mRNA levels of the putative suppressor gene H19 on 11p15.5 were decreased in 10 of 12 tumors, indicating that KIP2 and H19 are not co-regulated in HBs. IGF2 mRNA expression was increased in 11 of 12 HB samples. All HBs showed monoallelic KIP2 expression. However, the overexpression of KIP2 in HBs with maternal loss of 11p15.5 suggests a reactivation of the paternal allele in these cases. Overexpression of KIP2 in HBs argues against a role as a HB suppressor gene.
Child, Preschool↗
Expression of genes involved with cell cycle control, cell growth and chromatin modification are altered in hepatoblastomas.
Hepatoblastoma is a rare pediatric liver tumor. While much progress has been made in the treatment of the disease, very little is known about the moleculer events underlying the pathogenesis of this disease. We sought to investigate a series of hepatoblastomas for alterations in gene expression patterns with emphasis on important cell regulatory genes, including chromatin modifying enzymes, cyclin dependent kinase inhibitors, growth factors, oncogenes and cell cycle regulators. Total RNA was extracted from a series of sporadic hepatoblastomas with matched normal liver, some unmatched tumors and fetal livers, and gene expression was measured for various genes using RNase Protection Analysis (RPA). The results of this analysis show that the expression of many important regulatory genes are distinctly altered in these tumors, and a subset of tumors can be distinguished on the basis of these gene expression differences and histopathological features. Because the molecular events underlying the pathogenesis of this rare tumor are so poorly understood, this study represents a first step in determining some of the possible mechanisms involved which may provide future avenues of research.
Case-Control Studies↗
IGF-II enhances trichostatin A-induced TGFbeta1 and p21(Waf1,Cip1, sdi1) expression in Hep3B cells.
Cell growth and division are controlled through the actions of cyclin-dependent kinases (CDKs) and cyclin dependent kinase inhibitors (CKIs). Treatment of cell lines with Trichostatin A leads to induction of one of these CKIs, p21, and growth arrest. Induction of p21 can also occur through the actions of TGFbeta1. Latent TGFbeta1 can be activated by the M6P/IGF2R. In the present study we have examined the effect of TSA on members of the IGF axis, the CKIs p21 and p27, and also TGFbeta1 in Hep3B cells. The only member of the IGF axis to be affected by treatments was IGF2. Expression of another gene from the same chromosomal location, H19, was also affected. TGFbeta1 expression was greatly enhanced by TSA. In addition, both CKIs, p21 and p27, were upregulated by TSA. Effects of adding IGF-II or TGFbeta1 to TSA-treated cells on p21 induction were examined. The results show that the induction of p21 by TSA can be modulated by additions of IGF-II whereas addition of TGFbeta1 affects its own expression but not p21. In conclusion, the results indicate that the induction of p21 and cell growth arrest caused by Trichostatin A may involve multiple signaling pathways.
Apoptosis↗
An inhibitor-free assay of acetylcholinesterase and butyrylcholinesterase in the cerebrospinal fluid.
An inhibitor-free assay for the simultaneous determination of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the cerebrospinal fluid (CSF) is described. It is based on our finding that the individual activity ratios of BChE on both its substrates acetylthiocholine (ACh) and butyrylthiocholine (BCh) in the CSF and in the parallel serum are identical under conditions of at least 5 mmol/l substrate concentration (Q(BChE)SE = Q(BChe)CSF). Considering that AChE only reacts with ACh as substrate and occurs with negligible activities in the serum, the measured individual activity ratio of BChE in the serum (Q(BChE)SE) and the total hydrolysis rate of ACh and BCh in the CSF do allow a precise calculation of the AChE activity in the cerebrospinal fluid. The derivation of the corresponding formula is demonstrated in detail. The inhibitor-free assay was compared with procedures using cholinesterase inhibitors (BW284c51 for AChE and/or iso-OMPA for BChE). Achieving widely identical results in particular between the procedure using the AChE inhibitor and the inhibitor-free test, the latter has decisive advantages: (1) it avoids the use of highly toxic inhibitors, (2) it minimizes the test volume needed, (3) it characterizes additionally the status of the blood-CSF barrier by means of the BChE activity ratio in the CSF and in the parallel serum.
Acetylcholinesterase↗
[Treatment of stage IIIB loco-regionally advanced non-small-cell bronchial carcinomas with radiation and interferon-beta. Preliminary results of a phase II study].
BACKGROUND: In-vitro and in-vivo studies demonstrated the radiosensitizing effect of interferon beta on malignant tumor tissue as well as simultaneously a radioprotective effect on normal lung tissue. In this phase II study the outcome of combining radiotherapy with interferon beta in patients with advanced non-small cell lung cancer was evaluated. PATIENTS AND METHOD: From February 1994 until November 1996 14 patients with non-small cell lung cancer, stage IIIB were treated with locoregional radiation up to 59.4 Gy, with daily doses of 1.8 Gy and 5 fractions per week. Five million units of interferon beta (Fiblaferon) were given intravenously immediately preceding radiotherapy on the first 3 days of week 1, 3 and 5. RESULTS: Four of 14 patients (28.6%) showed complete response and 7 patients (50%) partial response, resulting in an overall response rate of 78.6%. After a mean follow-up time of 23.3 months the 1-, 2- and 3-year survival rates were 56.3%, 37.5% and 37.5%, respectively. The median survival time was 13 months. Three of 14 patients (21.4%) suffered from 7 Grade-3 acute side effects and 2 patients (14.3%) from 1 Grade-3 late toxicity in each case. One further patient, whose right lung was resected 3 months after completion of radiotherapy, developed as a consequence of this operation 2 Grade-4 complications. CONCLUSION: Considering the toxicity and the preliminary results of combining irradiation and interferon beta in the treatment of locally advanced non-small cell lung cancer it seems, that this procedure is worth to be tested in a phase III study.
Adult↗
[Motor activity and subjective findings in depressive patients].
Intensity of symptoms including mood and psychomotor activity has been shown to vary according to the time of the day in a group of depressed patients. This pattern represents one diagnostic criterion for the melancholic type of depression. The variation of intensity is experienced by the patient and can be observed as a behavioral symptom. However, the relation of circadian alterations in psychomotor activity and depressed mood remains unclear. Therefore, spontaneous motor activity and experienced intensity of symptoms were measured in 21 depressed patients who showed daily variations of subjective symptoms. Patients felt significantly less active, awake, and more depressed in the morning compared to the evening. However, corresponding activity levels, which were measured by actigraphy, appeared significantly higher in the morning compared to the evening. Increased motor activity could represent the observable behavioral equivalent of self-experienced psychomotor retardation and depressed mood.
Adult↗
Breeding of plums and prunes resistant to plum pox virus.
At Hohenheim we started a plum breeding programme to get new sharka-resistant cultivars with better fruit quality. In the last years we have recognized that the resistance of all cultivated plums is based on quantitative criteria and therefore relative. For this reason we changed our strategy for the resistance breeding. For the first breeding cycle we used special donors with quantitative resistance. Today, the qualitative resistance is more integrated. We intend to combine both types of resistance in the hexaploid genome of Prunus domestica to obtain an absolute and durable resistance. To achieve this aim, we have to consider the evaluation of resistance, the genetic resources, the inheritance of the resistance and also the breeding methods. The results of our resistance breeding study are presented.
Agriculture↗
Motor activity and daily variation of symptom intensity in depressed patients.
Spontaneous motor activity measured by actigraphy and subjectively experienced intensity of symptoms were investigated in 16 unipolar depressed inpatients with melancholic features. Patients felt significantly less active, awake, and more depressed in the morning compared to the evening. However, morning activity levels appeared significantly higher compared to evening levels. Diurnal variations of symptoms were reflected by actigraphically measured motor activity, which was negatively correlated with subjectively experienced symptom intensity. Increased motor activity may represent an observable, psychobiological, behavioral equivalent of self-experienced depressive symptoms in major depression with melancholic features.
Adult↗
XUV amplification in a recombining z-pinch plasma.
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Journal Article↗
[Fetal version as ambulatory intervention].
The external cephalic version (ECV) of the fetus at term reduces the maternal and fetal risks of intrapartum breech presentation and Caesarean delivery. Since 1986 over 800 external cephalic versions were performed in the outpatient Department of Obstetrics and Gynaecology of the Städtische Frauenklinik Stuttgart. 60.5% were successful. NO severe complications occurred. Sufficient amniotic fluid as well as the mobility of the fetal breech is a major criterion for the success of the ECV. Management requires a safe technique for mother and fetus. This includes ultrasonography, elektronic fetal monitoring and the ability to perform immediate caesarean delivery as well as the performance of ECV without analgesicas and sedatives. More than 70% of the ECV were successful without tocolysis. In unsuccessful cases the additional use of tocolysis improves the success rate only slightly. Therefore routine use of tocolysis does not appear necessary. External cephalic version can be recommended as an outpatient treatment without tocolysis.
Adult↗