Biomedical subjects

M Becker

Publications and source records attributed to M Becker.

At least 55 records · Page 3Linked to original sources

PubMed2000

[Value of positron emission tomography with 18-fluorodeoxyglucose (FDG-PET) in early detection of residual tumor in oro-pharyngeal-laryngeal carcinoma].

OBJECTIVE: To evaluate and compare the performances of FDG-PET imaging, MRI and clinical examination in the detection of residual tumour 3 months after treatment of patients with head and neck squamous cell carcinoma. PATIENTS: A consecutive sample of 50 patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, or a cervical lymph node metastasis from an unknown primary site excluding T1 lip and T1 vocal cord tumours. METHODS: Treatment outcome was assessed after 3 months by clinical examination, MRI, and FDG-PET scan. Sensitivity, specificity and accuracy were calculated relative to proven biopsy of residual tumour or a clinical follow-up of 4 months. RESULTS: Residual cancer was confirmed in 8 patients (16%), while the clinical follow-up was unsuspicious in the remaining 42 patients. PET-FDG had a sensitivity of 100% as compared to MRI (88%) and clinical examination (63%). Specificity was higher for clinical examination (90%), intermediate for MRI (83%) and lowest for PET-FDG (74%). CONCLUSIONS: This study finds very high sensitivity for PET-FDG in the detection of residual tumour. However, its lower specificity, lack of anatomical resolution, and high cost, require further studies to determine its role in routine screening.

Biopsy↗

PubMed2000

A phase II study of biochemotherapy for the treatment of metastatic malignant melanoma.

The use of interleukin-2 (IL-2) and interferon-alpha (IFNalpha) in combination with chemotherapy for the treatment of advanced malignant melanoma has generated considerable interest. In particular, the relatively high number of durable complete responses has suggested this may be a significant advance in the treatment of malignant melanoma. We report our experience at the University of Colorado in 43 patients, including many with poor prognostic factors. Patients received cisplatin 20 mg/m2 on days 1-4, vinblastine 1.6 mg/m2 on days 1-4, dacarbazine 800 mg/m2 on day 1, IL-2 9 x 10(6) IU/m2 per day intravenously over 24h on days 1-4 and IFNalpha 5 x 10(6) IU/m2 per day subcutaneously on days 1-5 every 3 weeks. The median follow-up for all patients was 34 months. Responses were seen in 20 patients (47%, 95% confidence interval 31-62%) and comprised five complete responses (CRs) (12%) and 15 partial responses (PRs) (35%). Two patients achieving a CR remain disease free at 45 and 47 months follow-up. In addition three patients who obtained a surgical CR and another with only minor residual changes on computed tomography scan have not progressed at 27, 30, 40 and 27 months, respectively. Toxicity was manageable, but all patients had at least one grade 3 or 4 toxicity, predominantly hypotension and neutropenia. There were no treatment-related deaths. In conclusion, the response rate and duration is within the range previously reported for biochemotherapy. The results of ongoing randomized studies are awaited to better define the value of biochemotherapy in the treatment of advanced melanoma.

Abdominal Neoplasms↗

PubMed2000

Direct comparison of F-18-FDG PET and ultrasound in the follow-up of patients with squamous cell cancer of the head and neck.

AIM: The objective of this study was to compare screening ultrasound (US) obtained in patients with squamous cell carcinoma of the head and neck with F-18-FDG PET and to evaluate if US obtained before F-18-FDG PET has the potential to enhance patient management by the detection of additional lesions. METHOD: 28 patients were prospectively included in the study (7 females and 21 males; range: 28-82 years). All had one follow-up examination after surgical treatment and/or radiotherapy using a combination of US and F-18-FDG PET on the same day (6-35 months after the end of treatment). Outcome was determined by either biopsyproven cancer recurrence or negative clinical follow-up for additional 6 months after this examination. RESULTS: Regarding only the regions of the neck evaluated with both methods, US detected 25 suspect lesions vs. 9 lesions detected by F-18-FDG PET. Descriptive statistical analysis showed better sensitivity, specificity and accuracy of F-18-FDG PET. Only in 3 patients a lesion was detected in the same anatomical region using both methods. One patient was false positive with both methods. In another patient US detected a calcified right carotid artery plaque that lead to surgical therapy. CONCLUSION: F-18-FDG PET is better for the detection of clinically relevant lesions in the follow-up of patients with squamous cell carcinoma of the head and neck. In this study, the additional value of morphological information obtained by screening US performed before the PET scan is limited. US may not be a suitable test to improve interpretation of PET examinations.

Adult↗

PubMed1999

Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team.

BACKGROUND: Consistent long-term viral suppression has been difficult to achieve in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested the safety and antiviral efficacy of a novel combination consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57 children previously treated with only nucleoside reverse-transcriptase inhibitors. METHODS: The children were monitored for 48 weeks after the initiation of therapy. We assessed plasma concentrations of efavirenz and nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations. RESULTS: At base line, the 57 HIV-1-infected children (age range, 3.8 to 16.8 years) had a median of 699 CD4 cells per cubic millimeter and 10,000 copies of HIV-1 RNA per milliliter of plasma. The most common treatment-related effects of at least moderate severity were rash (in 30 percent of children), diarrhea (in 18 percent), neutropenia (in 12 percent), and biochemical abnormalities (in 12 percent). Serious side effects were uncommon. The mean values for the area under the curve for efavirenz and nelfinavir corresponded to expected values. In an intention-to-treat analysis, 76 percent of children had plasma HIV-1 RNA levels of less than 400 copies per milliliter after 48 weeks of therapy and 63 percent had levels of less than 50 copies per milliliter. A high plasma HIV-1 RNA level at base line significantly decreased the likelihood that plasma levels of HIV-1 RNA would become undetectable during treatment. CONCLUSIONS: In HIV-1-infected children who were previously treated with nucleoside reverse-transcriptase inhibitors, the combination of efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was generally well tolerated and had a potent and sustained antiviral effect.

Adolescent↗

PubMed1999

Amplification of the mdr1-gene is uncommon in recurrent ovarian carcinomas.

Ovarian carcinomas are known to rapidly develop drug resistance against chemotherapeutic agents. This phenomenon is often associated with the expression of pl70-glycoprotein. A high rate of transcription of the corresponding mdr1-gene in resistant tumors is reported. Amplification of the mdr1-gene has been observed in tumor cell lines exposed to cytotoxic drugs; however, significant information is lacking as to whether this holds true in clinical carcinomas. To fill this gap, we investigated the rate of gene amplification of the mdr1-gene in 63 recurrent ovarian carcinomas and we determined the resistance pattern of these cells using an ex vivo assay. The tumors showed varying ex vivo resistance patterns which did not correlate to clinical parameters. Amplification of the mdr1-gene was not observed in any of the cancer specimens. Therefore, we conclude that mdr1-gene amplification is not a common pathway for the development of chemoresistance in clinical ovarian carcinomas.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Rapid signalling by androgen receptor in prostate cancer cells.

Androgens are important growth regulators in prostate cancer. Their known mode of action in target cells requires binding to a cytoplasmic androgen receptor followed by a nuclear translocation event and modulation of the expression of specific genes. Here, we report another mode of action of this receptor. Treatment of androgen responsive prostate cancer cells with dihydrotestosterone leads to a rapid and reversible activation of mitogen-activated protein kinases MAPKs (also called extracellular signal-regulated kinases or Erks). Transient transfection assays demonstrated that the androgen receptor-mediated activation of MAP kinase results in enhanced activity of the transcription factor Elk-1. This action of the androgen receptor differs from its known transcriptional activity since it is rapid and insensitive to androgen antagonists such as hydroxyflutamide or casodex. Biochemical studies as well as analyses with dominant negative mutants showed the involvement of kinases such as MAPK/Erk kinase, phosphatidyl-inositol 3-kinase and protein kinase C in the androgen receptor-mediated activation of MAP kinase. These results demonstrate a novel regulatory action of the androgen receptor and prove that in addition to its known transcriptional effects, it also uses non-conventional means to modulate several cellular signalling processes.

Adenocarcinoma↗

PubMed1999

Drainin required for membrane fusion of the contractile vacuole in Dictyostelium is the prototype of a protein family also represented in man.

The contractile vacuole expels water by forming a channel with the plasma membrane and thus enables cells to survive in a hypo-osmotic environment. Here we characterize drainin, a Dictyostelium protein involved in this process, as the first member of a protein family represented in fission yeast, Caenorhabditis elegans and man. Gene replacement in Dictyostelium shows that drainin acts at a checkpoint of channel formation between the contractile vacuole and the plasma membrane. A green fluorescent protein fusion of drainin localizes specifically to the contractile vacuole and rescues its periodic discharge in drainin-null cells. Drainin is a peripheral membrane protein, requiring a short hydrophobic stretch in its C-terminal region for localization and function. We suggest that drainin acts in a signaling cascade that couples a volume-sensing device in the vacuolar membrane to the membrane fusion machinery.

Amino Acid Sequence↗

PubMed1999

Author errata.

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Retraction Notice↗

PubMed1999

Alterations of intratumoral pharmacokinetics of 5-fluorouracil in head and neck carcinoma during simultaneous radiochemotherapy.

The kinetics of local drug uptake and metabolism of the anticancer drug 5-fluorouracil (5-FU) has been monitored by means of 19F nuclear magnetic resonance spectroscopy in 17 patients with neck tumors during concurrent radiochemotherapy. All of the patients underwent an accelerated hyperfractionated, concomitant-boost radiochemotherapy with 5-FU [600 or 1000 mg/m2 of body surface (b.s.)] and carboplatin (70 mg/m2 of b.s.). Serial 19F nuclear magnetic resonance spectra were obtained during and after the administration of 5-FU in a 15-T scanner with the use of a 5-cm diameter surface coil positioned on a cervical lymph node metastasis. Examinations were performed at day 1 of therapy and, in 13 patients, also after 43.5 Gy of irradiation at day 1 of the second chemotherapy cycle. Resonances of 5-FU and the catabolites 5,6-dihydro-5-fluorouracil (DHFU) and alpha-fluoro-beta-alanine (FBAL) were resolved in the tumor spectra. The median of the 5-FU and FBAL levels was significantly higher (more than 2-fold) at the second compared with the first examination, whereas the level of DHFU did not change. This effect could indicate an increased delivery of 5-FU into the interstitial space of the tumor in the course of the combined treatment, which would result in an enhanced exposure of the tumor cells to the drug. A potential mechanism for synergy between radio- and chemotherapy is discussed, but alternative mechanisms are also being considered. The findings indicate that a method is available to rationally address the design of dosing schedules in concurrent therapy regimens.

Adult↗

PubMed1999

The double helix is dehydrated: evidence from the hydrolysis of acridinium ester-labeled probes.

A highly chemiluminescent reporter molecule, acridinium ester (AE), was tethered to single-stranded oligonucleotide probes and hybridized to complementary as well as mismatched target sequences. When tethered to single-stranded probes, AE was readily hydrolyzed by water or hydroxide ion. In contrast, when hybridized to a complementary target, hydrolysis of the AE probe was markedly inhibited. Mismatches near AE eliminated the ability of the double helix to strongly inhibit AE hydrolysis. To establish the molecular basis for these remarkable hydrolysis properties of AE-labeled probes, the binding and hydrolysis mechanisms of AE-labeled probes were examined. When tethered to single- or double-stranded nucleic acids, hydrolysis of AE was found to proceed by generalized base catalysis in which a base abstracts a proton from water and the resulting hydroxide ion then hydrolyzes AE. Analysis of the hydrolysis rates of AE bound to DNA revealed that AE binds the minor groove of DNA and that its hydrolysis is inhibited by low water activity within the minor groove of the helix. Depending upon the sequence of the DNA, the water activity of the minor groove was estimated to be at least 2-4-fold lower than bulk solution. Hydrolysis measurements of AE tethered to RNA as well as RNA/DNA hybrids argued that the grooves of these double helices are also dehydrated relative to bulk solution. Remarkably, mismatched bases, regardless of their structure or sequence context, enhanced hydrolysis of AE by inducing hydration of the double helix that spread approximately five base pairs on either side of the mismatch.

Acridines↗

PubMed1999

Both AP-1 and Cbfa1-like factors are required for the induction of interstitial collagenase by parathyroid hormone.

PTH is a major regulator of calcium homeostasis by mobilizing calcium through bone resorption. We show that the expression of collagenase-3 (MMP-13), a member of the family of matrix metalloproteinases, required for the cleavage of collagens in the bone, is increased upon PTH injection in mice. A cis-acting element in the collagenase-3 promoter was identified which, together with AP-1, is required for induction by PTH. This element contains CCACA motifs which are required for binding of the 65 kDa osteoblast-specific splice variant of Cbfal. Introduction of mutations in this binding site that interfere with protein interaction also eliminates PTH inducibility and transactivation by Cbfa/ Runt proteins. While DNA binding activity of AP-1 is increased upon PTH treatment, high basal level of Cbfa/Runt binding activity is detectable in untreated cells which is not further increased by PTH, suggesting that AP-1 and Cbfal contribute to transcriptional activation through different mechanisms. In agreement with the critical role of both proteins defined in tissue culture cells, expression of collagenase-3 is reduced in mice lacking c-fos and is completely absent in cbfa1-/-embryos. These data provide the first evidence for a critical role of Cbfal, a major regulator of bone development, in PTH-dependent processes such as bone resorption.

Animals↗

PubMed1999

Internal carotid artery dissection following rigid esophagoscopy.

A case of internal carotid artery dissection that developed after rigid esophagoscopy is described. The diagnosis was suggested by the clinical presentation and confirmed by the findings of radiological examinations. Internal carotid artery dissection is a rare condition of controversial etiology. Most frequently, the cause is unknown and the condition is termed idiopathic. A few cases have occurred after forceful cervical extensions and manipulations. The pathogenesis in our case is uncertain: while the rigid esophagoscopy is the most probable cause, the intubation and spontaneous carotid artery dissection cannot be ruled out.

Adult↗

PubMed1999

Viability of cultured nerve grafts: An assessment of proliferation of Schwann cells and fibroblasts.

Previous studies demonstrated that the viability of nerve grafts had a positive effect on nerve regeneration, while the cold storage of nerve grafts obtained few viable cells at the later stage. The purpose of this study was to examine the cellular activities of Schwann cells and fibroblasts in cultured nerve grafts prior to transplantation. 2.5-cm long sciatic nerve grafts were harvested from 75 male Lewis rats. Two different media were utilized to culture the nerve grafts up to 3 weeks: Dulbecco's modified eagle medium (DMEM) only or DMEM supplemented with 2 microM forskolin and 10 microg/ml pituitary exact (mitogen medium for Schwann cells). In vivo predegenerated and normal nerve grafts were used as positive and negative controls, respectively. We employed a 5-bromo-2'-deoxyuridine (BrdU) incorporation method to evaluate the proliferating cells in the cultured nerve grafts. S-100 and vimentin immunostaining were used to estimate the presence of Schwann cells and fibroblasts in all nerve grafts at different intervals. The results showed that the proliferating cells increased progressively under culture conditions. The proliferating cells distributed evenly in small fascicles (average diameter 251 +/- 71.5 microm), whereas they appeared mainly in the margin of large fascicles (average diameter 624 +/- 87.3 microm). The mitogen medium stimulated Schwann cell multiplication more significantly in comparison with DMEM after 3 days of culture (P < 0.01), however, there were fewer fibroblasts present in the mitogen medium than in DMEM after 2 days of culture (P < 0.01). It is suggested that the viability of nerve grafts can be preserved under culture conditions. Furthermore, the cellular activity of the Schwann cells and fibroblasts in nerve grafts can be manipulated in in vitro Wallerian degeneration.

Animals↗

PubMed1999

Differential kinetics of primitive hematopoietic cells assayed in vitro and in vivo during serum-free suspension culture of CD34+ blood progenitor cells.

So far, blood progenitor cells (BPC) expanded ex vivo in the absence of stromal cells have not been demonstrated to reconstitute hematopoiesis in myeloablated patients. To characterize the fate of early hematopoietic progenitor cells during ex vivo expansion in suspension culture, human CD34(+)-enriched BPC were cultured in serum-free medium in the presence of FLT3 ligand (FL), stem cell factor (SCF) and interleukin 3 (IL-3). Both CD34 surface expression levels and the percentage of CD34+ cells were continuously downregulated during the culture period. We observed an expansion of colony-forming units granulocyte-macrophage (CFU-GM) and BFU-E beginning on day 3 of culture, reaching an approximate 2-log increase by days 5 to 7. Limiting dilution analysis of primitive in vitro clonogenic progenitors was performed through a week 6 cobblestone-area-forming cell (CAFC) assay, which has previously been shown to detect long-term bone marrow culture-initiating cells (LTC-IC). A maintenance or a slight (threefold) increase of week 6 CAFC/LTC-IC was found after one week of culture. To analyze the presence of BPC mediating in vivo engraftment, expanded CD34+ cells were transplanted into preirradiated NOD/SCID mice at various time points. Only CD34+ cells cultured for up to four days successfully engrafted murine bone marrow with human cells expressing myeloid or lymphoid progenitor phenotypes. In contrast, five- and seven-day expanded human BPC did not detectably engraft NOD/SCID mice. When FL, SCF and IL-3-supplemented cultures were performed for seven days on fibronectin-coated plastic, or when IL-3 was replaced by thrombopoietin, colony forming cells and LTC-IC reached levels similar to those of control cultures, yet no human cell engraftment was recorded in the mice. Also, culture in U-bottom microplates resulting in locally increased CD34+ cell density had no positive effect on engraftment. These results indicate that during ex vivo expansion of human CD34+ cells, CFC and LTC-IC numbers do not correlate with the potential to repopulate NOD/SCID mice. Our results suggest that ex vivo expanded BPC should be cultured for limited time periods only, in order to preserve bone-marrow-repopulating hematopoietic stem cells.

Animals↗

PubMed1999

Local disposition kinetics of floxuridine after intratumoral and subcutaneous injection as monitored by [19F]-nuclear magnetic resonance spectroscopy in vivo.

PURPOSE: To test the utility of [19F]-nuclear magnetic resonance (NMR) spectroscopy for studying the kinetics of local drug disposition after interstitial application in vivo. METHODS: Floxuridine at 30 micromol (2.5% of the reported i.p. 50% lethal dose, LD50) was injected into rats either intratumorally (Morris hepatoma M3924A) or s.c. [19F]-NMR spectra were obtained at the site of administration for up to 5 h after injection using a 2-cm diameter surface coil at 2.0 T. Signal-time data obtained for floxuridine and the metabolite 5-fluorouracil were analyzed using linear compartment models. RESULTS: The lower limit for the quantitation of drug remaining at the site of administration was 1 micromol for tumors and 0.2 micromol for the s.c. injection site. Local drug disposition was biexponential in four of six tumors where the half-lives of the fast and slow components of disposition ranged from 4 to 26 and from 33 to 289 min, respectively. It was monoexponential in the remaining two tumors (half-lives 49 and 128 min) and in the s.c. injection experiments (n = 4, half-life 6-9 min). 5-Fluorouracil could be quantitated in three of six tumors; the estimated fraction of floxuridine converted intratumorally into 5-fluorouracil was 11-23%. Alpha-fluoro-beta-alanine was detected in the sum spectra of three of the six tumours. CONCLUSIONS: Local drug-disposition kinetics after interstitial application can be monitored noninvasively by in vivo [19F]-NMR spectroscopy. Disposition kinetics after local injection is highly variable and has a slow component in this tumor, whereas it is much less variable and relatively fast in subcutaneous tissue. The results suggest that NMR spectroscopy may be useful for in vivo studies of drug release from depot preparations designed for interstitial application.

Animals↗

PubMed1999

A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis.

BACKGROUND & AIMS: In pancreatitis, a key role has been attributed to the inappropriate conversion of trypsinogen to trypsin. Recently, two mutations of the cationic trypsinogen gene were found in families with hereditary pancreatitis. This study was conducted to determine the spectrum and frequency of cationic trypsinogen mutations in unrelated patients with idiopathic or hereditary chronic pancreatitis (CP). METHODS: DNA samples from 44 unrelated children and adolescents with CP (30 patients with idiopathic CP and 14 with hereditary CP) and from 56 family members were investigated. The cationic trypsinogen gene was screened for mutations by single-strand conformation polymorphism analysis and DNA sequencing. RESULTS: A mutation in the cationic trypsinogen gene was detected in 5 patients: in 2 patients with a family history of CP and in 3 patients with idiopathic CP. In 1 patient the formerly described R122H mutation was detected. In 4 patients a hitherto unknown mutation was found at the signal peptide cleavage site leading to an alanine to valine exchange in codon 16. The mutations were inherited in all cases. In 95 unrelated control individuals the A16V mutation was not found. CONCLUSIONS: Heterozygosity for the A16V mutation is strongly associated with CP. These results indicate that a significant percentage of patients with idiopathic CP may have a genetic basis for their disorder; therefore, genetic testing should be included in the diagnostic evaluation of these patients.

Adolescent↗

PubMed1999

Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency.

Dysfunction of the alpha-tocopherol transfer protein causes ataxia with isolated vitamin E deficiency. A 14-year-old male patient presented with ataxia and mental symptoms caused by a homozygous (552G-->A) alpha-tocopherol transfer protein mutation. After initiation of high-dosage alpha-tocopherol therapy, the organic mental syndrome disappeared and cognitive function improved rapidly. Neurologic recovery, however, was slow and incomplete.

Adolescent↗

PubMed1999

Surgical treatment of Zenker's diverticulum: transcutaneous diverticulectomy versus microendoscopic myotomy of the cricopharyngeal muscle with CO2 laser.

In a retrospective study, we analyzed 97 patients who were treated by either transcutaneous diverticulectomy (n = 66) or microendoscopic myotomy of the cricopharyngeal muscle with CO(2) laser (n = 31). Two (6.4%) of 31 patients in the microendoscopic myotomy group had complications, compared with 10 (15%) of 66 patients in the diverticulectomy group. In addition, the complications observed in the microendoscopic myotomy group were less severe than those observed in the transcutaneous diverticulectomy group. The average length of hospitalization was shorter in the microendoscopic myotomy group than in the diverticulectomy group (8 days versus 11.4 days). We conclude that microendoscopic CO(2)-laser myotomy is a less invasive, more precise, and safer procedure, which results in a shortened period of hospitalization and complete relief of symptoms in the vast majority of cases.

Adult↗