Biomedical subjects

A Barth

Publications and source records attributed to A Barth.

At least 91 records · Page 5Linked to original sources

PubMed1995

Prognostic classification of breast ductal carcinoma-in-situ.

We present a new prognostic classification designated the Van Nuys classification for ductal carcinoma-in-situ (DCIS). The classification combines high nuclear grade and comedo-type necrosis to predict clinical recurrence. Three groups of DCIS patients were defined by the presence or absence of high nuclear grade and comedo-type necrosis: 1--non-high-grade DCIS without comedo-type necrosis, 2--non-high-grade DCIS with comedo-type necrosis, 3--high-grade DCIS with or without comedo-type necrosis. There were 31 local recurrences in 238 patients after breast-conservation surgery 3.8% (3/80) in group 1, 11.1% (10/90) in group 2, and 26.5% (18/68) in group 3. The 8-year actuarial disease-free survivals were 93%, 84%, and 61%, respectively (all p < or = 0.05). The Van Nuys classification defines three distinct and easily recognisable groups, each of which has a different likelihood of local recurrence if treated with breast conservation.

Bone Neoplasms↗

PubMed1995

Glycine site NMDA receptor antagonists provide protection against ischemia-induced neuronal damage in hippocampal slice cultures.

Ischemia-induced neuronal injury can be reduced by glutamate antagonists acting at the N-methyl-D-aspartate (NMDA) receptor. 7-Chlorokynurenic acid and the recently synthesized compound Acea 1021 block NMDA receptors by acting at the strychnine-insensitive glycine site. The anti-ischemic properties of these compounds were tested by evaluating their ability to reduce CA1 neuronal damage in hippocampal slice cultures deprived of oxygen and glucose. Acea 1021 and 7-chlorokynurenic acid significantly reduced CA1 injury produced by oxygen and glucose deprivation in a dose-dependent manner. The neuroprotective effect of these compounds was reversed by the addition of glycine. The phencyclidine site NMDA antagonist MK-801 also provided significant protection to CA1 neurons against the same insult, and this protection was not affected by the addition of glycine. These results indicate that Acea 1021 and 7-chlorokynurenic acid can provide protection to CA1 neurons against ischemia-induced injury by a glycine-sensitive mechanism.

Animals↗

PubMed1995

[Ductal carcinoma in situ of the breast].

With the advent of screening mammography, ductal carcinoma in situ (DCIS) is detected with increasing frequency and now accounts for 10-15% of all diagnosed breast cancers. Before 1980, DCIS was usually diagnosed by clinical findings of a breast mass or nipple discharge; today most cases are detected mammographically and nonpalpable. The most common mammographic findings associated with DCIS are a cluster of microcalcifications. The concept that DCIS invariably progresses to invasive breast cancer and requires mastectomy has been challenged. Knowledge of DCIS is limited and primarily based on retrospective data. Further insight will emerge from ongoing randomized prospective studies that are near completion. Currently available data indicate that breast-conserving modalities may offer a valid alternative to mastectomy in selected patients with DCIS.

Breast Neoplasms↗

PubMed1995

The role of adjuvant therapy in melanoma management.

Adequate wide excision of a primary cutaneous melanoma is associated with a 10-year cure rate of 85% when the tumor's depth is less than 1.5 mm (American Joint Committee on Cancer [AJCC] Stage I). However, 50% of patients with deep (> 4 mm) primary melanomas, 60-85% of those with regional lymph node metastases (AJCC Stage III), and 95% of those with metastases to distant sites (AJCC Stage IV) will experience recurrence, which is associated with a dismal prognosis. Adjuvant therapy of melanoma assumes that treatment will be more effective when the tumor burden is small. In the 1970s and 1980s, randomized trials tested the efficacy of chemotherapy, nonspecific immunotherapy, levamisole, and regional perfusion therapy in patients with AJCC Stage II and III melanoma. Dacarbazine (DTIC) alone or in combination with other chemotherapeutic drugs or with nonspecific immunotherapy did not significantly improve disease free or overall survival. Of the four levamisole trials, only the study conducted by the National Cancer Institute of Canada revealed a reduction in recurrence and mortality; however, this reduction was not significant by multivariate analysis. The value of regional perfusion therapy following resection of high risk extremity melanomas is currently being determined by multiinstitutional studies conducted by the World Health Organization and the North American Perfusion Group. Multi-institutional trials also are examining the adjuvant role of interferon-alpha in patients with deep (> 3 mm) primary melanomas or positive regional lymph nodes; results should reveal its optimum dose and duration of treatment (3 x 10(6) U for > or = 2 years versus 10 x 10(6) U/m2 for 1 year, subcutaneously 3 times a week) and its impact on survival. A randomized trial of interferon-gamma undertaken by the Southwest Oncology Group was discontinued after interim analysis indicated an adverse effect. Phase II trials indicate that active specific immunotherapy can alter the natural course of AJCC Stage III and IV melanoma following surgical resection of nodal or distant metastases. Upcoming results of Phase III trials will establish the role of active specific immunotherapy for adjuvant treatment of patients with resected AJCC Stage III and IV melanoma.

BCG Vaccine↗

PubMed1995

Ten-year results comparing mastectomy to excision and radiation therapy for ductal carcinoma in situ of the breast.

The 10-year results of 300 patients with ductal carcinoma in situ (DCIS) without microinvasion are reported; 167 treated with mastectomy and 133 treated with excision and radiation therapy. There was a significant difference in disease-free survival at 10 years, in favour of those treated with mastectomy, 98% versus 81% (P = 0.0004). Multivariate analysis confirmed nuclear grade as the only significant predictor of local recurrence (P = 0.02) or invasive local recurrence (P = 0.03) in patients with DCIS treated with excision and radiation therapy. There was no difference in breast cancer-specific survival or overall survival between the two treatment groups.

Adult↗

PubMed1995

Brain peroxidative and glutathione status after moderate hypoxia in normal weight and intra-uterine growth-restricted newborn piglets.

In order to investigate the pathogenetic factors causing the relatively frequent occurrence of brain injury in intrauterine growth-restricted newborns, lipid peroxidation products (TBAR), glutathione (GSH, GSSG) and in vitro production of reactive oxygen species (chemiluminescence, stimulated lipid peroxidation, H2O2 formation) were studied in the brain of normal weight (NW) and intra-uterine growth-restricted newborn piglets (IUGR) after 1 hour of hypoxia (FiO2 11%) and 90 min reoxygenation. Cardiocirculatory parameters and catecholamine release into the blood were also measured. In the cerebellum, higher GSH content, but also higher in vitro production of lucigenin amplified chemiluminescence were found in comparison to other brain regions, independent of growth restriction and hypoxia. Moderate hypoxia without acidosis and hypercapnia resulted in GSH depletion especially in the brain of IUGR, but no changes in GSSG concentrations were measured. Though TBAR decreased after hypoxia/reoxygenation, in some brain areas of IUGR higher TBAR values were found in comparison to NW. H2O2 formation, stimulated lipid peroxidation and lucigenin and luminol amplified chemiluminescence in the 9000 x/g supernatant of brain tissue did not reveal special response of IUGR to hypoxia/reoxygenation. Hypoxia-induced circulatory centralisation due to increased release of catecholamines into the plasma prevented oxygen deficiency also in the brain of IUGR. The role of brain monoamine metabolism in the production of reactive oxygen species, followed by greater GSH depletion and higher in vivo formation of lipid peroxides in IUGR is discussed.

Animals↗

PubMed1995

CoMFA investigations on two series of artificial peptide inhibitors of the serine protease thermitase. Synthesis of an inhibitor of predicted greater potency.

Comparative molecular field analysis (CoMFA) is shown to be a very useful tool in treating two series of artificial substrate analogue inhibitors, peptide methyl ketones and chloromethyl ketones, of the serine protease thermitase. The backbone structure of the native polypeptide eglin c found in the X-ray structure of its complex with the enzyme served as a template for the alignment of the inhibitors, which could be shown to be the key for success. Restricted only by the relatively small number of different amino acids representing the peptide sequence we were able to determine the regions of the compounds that are important for the value of the inhibitor constant K(i). On the basis of these results we have suggested some new structures with possibly increased inhibitory activity. One such structure was synthesized and is shown to be the most active compound tested up to now, with an experimental K(i)-value in the predicted range.

Amino Acid Sequence↗

PubMed1995

A model of the active site of dipeptidyl peptidase IV predicted by comparative molecular field analysis and molecular modelling simulations.

A molecular model of the active site of the serine protease dipeptidyl peptidase IV (DPP IV or CD26) has been developed on the basis of comparative molecular field analysis (CoMFA) of competitive inhibitors and by force field calculations. By application of CoMFA experimentally obtained inhibition constants Ki have been successfully predicted. The resulting steric and electrostatic coefficients of CoMFA were used for the development of the molecular model. The main assumptions of the model are the recognition of substrates or inhibitors by the side chains of a tyrosine (S1-position) and a tryptophan residue (S2-position). The model helps us to understand a multitude of experimental data regarding the substrate specificity of this enzyme as well as results obtained by genetic engineering experiments by other authors. General conclusions concerning a new family of serine proteases are drawn and discussed.

Binding Sites↗

PubMed1995

Glutamate and non-glutamate receptor mediated toxicity caused by oxygen and glucose deprivation in organotypic hippocampal cultures.

In vitro ischemia models have utilized oxygen, or oxygen and glucose deprivation to simulate ischemic neuronal injury. Combined oxygen and glucose deprivation can induce neuronal damage which is in part mediated through NMDA receptors. Severe oxygen deprivation alone however can cause neuronal injury which is not NMDA mediated. We tested the hypothesis that NMDA, or non-NMDA receptor mediated mechanisms may predominate, to induce neuronal injury following severe oxygen deprivation depending on the presence of glucose. We found that NMDA receptor blockade using dizocilpine (MK-801), DL-2-amino-5-phosphonovaleric acid (APV), or CGS 19755, was highly effective in reducing CA1 injury in organotypic hippocampal cultures, caused by complete oxygen and glucose deprivation. Complete oxygen deprivation alone however, caused CA1 neuronal injury which was not diminished using NMDA receptor blockade alone with MK-801 or APV, or in combination with AMPA/kainate receptor blockade using 6-cyano-7-dinitroquinoxalone-2,3-dione (CNQX). Neuronal protective strategies which act primarily through non-glutamate dependent mechanisms, including hypothermia, low chloride and calcium, and the free radical scavenger, alpha-phenyl-tert-butyl nitrone (PBN), provided neuronal protection against complete oxygen, as well as combined oxygen/glucose deprivation. Raising the pH using Hepes buffer during complete oxygen deprivation did not result in neuronal protection by NMDA receptor blockade. Partial oxygen deprivation alone, partial oxygen deprivation combined with glucose deprivation, glucose deprivation alone, and also glutamate exposure, all produced neuronal damage that was reduced by NMDA receptor blockade. The presence of glucose during complete oxygen deprivation appears to prevent glutamate receptor blockade from reducing neuronal injury in organotypic hippocampal cultures.

Animals↗

PubMed1995

Current management of ductal carcinoma in situ.

Ductal carcinoma in situ represents a biologically and histologically heterogeneous group of lesions characterized by the proliferation of neoplastic epithelial cells confined to the ducts of the breast. Before screening mammography, ductal carcinoma in situ was considered uncommon; patients were usually diagnosed by a breast mass or bloody nipple discharge, and their treatment was mastectomy. Today it represents 20% to 30% of mammographically detected breast cancers and 10% to 15% of all diagnosed breast cancers in the United States. The invariable progression of this cancer to invasive breast cancer requiring mastectomy has been challenged, but because most patients have been treated with mastectomy, knowledge about ductal carcinoma in situ is limited and primarily based on retrospective data. Further insight will emerge from randomized prospective studies that are near completion. Currently available data indicate that breast-conserving treatments are valid alternatives to mastectomy for most patients with this disease.

Breast Neoplasms↗

PubMed1995

Prognostic factors in 1,521 melanoma patients with distant metastases.

BACKGROUND: Although over 7,000 people die from malignant melanoma each year, there are limited prognostic data for patients with metastatic disease. A retrospective analysis was undertaken to identify variables that accurately predict outcome and to determine if the survival rate of patients with melanoma treated for distant metastases (American Joint Committee on Cancer [AJCC] stage IV disease) at the authors' institution changed between 1971 and 1993. STUDY DESIGN: Data for 1,521 patients with AJCC stage IV melanoma treated by the staff of the John Wayne Cancer Institute were reviewed, and a univariate and multivariate survival analysis against ten clinical and pathological variables was performed using the Cox proportional hazard regression model. RESULTS: The median survival time of the 1,521 patients was 7.5 months; the estimated five-year survival rate was 6 percent. Three independent variables predicted survival: initial site of metastases (p < 0.0001); disease-free interval before distant metastases (p = 0.0001); and stage of disease preceding distant metastases (p = 0.0001). Patients could be divided into three distinct prognostic groups based on the initial site of metastases: cutaneous, nodal, or gastrointestinal metastases (median survival of 12.5 months; estimated five-year survival rate 14 percent); pulmonary metastases (median survival of 8.3 months; estimated five-year survival rate 4 percent); and metastases to the liver, brain, or bone (median survival of 4.4 months; estimated five-year survival rate 3 percent). There was no significant change in the survival rate of patients with AJCC stage IV melanoma during the 22-year review period. CONCLUSIONS: Despite new treatment options, the survival rate of patients with metastatic melanoma has not changed significantly over the last 22 years; their prognosis remains dismal. The three prognostic variables identified in this study should be considered in the design of future clinical trials.

Adolescent↗

PubMed1995

Somatostatin receptor scintigraphy in central nervous system tumors: role of blood-brain barrier permeability.

UNLABELLED: Somatostatin receptors are expressed in meningiomas and low-grade gliomas, raising the hope that scintigraphy with 111In-DTPA-D-Phe1-octreotide might be helpful in the in vivo localization, differential diagnosis and postoperative/postradiotherapy brain tumor follow-up. METHODS: Indium-111-DTPA-D-Phe1-octreotide scintigraphy and brain scintigraphy using 99mTc-DTPA as a nonspecific tracer for blood-brain barrier integrity were simultaneously performed in 60 patients with CNS tumors using dual-isotope acquisition mode SPECT. For 23 patients, the scintigraphic findings were also compared with in vitro somatostatin receptor autoradiography of surgical biopsy specimens. RESULTS: In meningiomas (located outside the blood-brain barrier), the somatostatin receptor scan showed all tumors and scintigraphic signal intensity correlating with in vitro SSR density positive in all meningiomas. Less contrast was seen on 99mTc-DTPA scans. In all tumors inside the blood-brain barrier, the 111In-DTPA-D-Phe1-octreotide scan visualized the tumors with a disrupted blood-brain barrier, as seen by 99mTc-DTPA scintigraphy. Discrepancies, however, were observed between somatostatin receptor scintigraphy and in vitro receptor autoradiography. CONCLUSION: Combined somatostatin receptor and 99mTc-DTPA scintigraphy may be helpful for noninvasive differentiation between meningiomas and other CNS tumors. False-negative scans were observed as a result of shielding by the intact blood-brain barrier. Interpretation of negative and positive somatostatin receptor scans in CNS tumors must therefore be done with caution.

Adolescent↗

PubMed1994

Structural changes of sarcoplasmic reticulum Ca(2+)-ATPase upon Ca2+ binding studied by simultaneous measurement of infrared absorbance changes and changes of intrinsic protein fluorescence.

Ca2+ binding to sarcoplasmic reticulum Ca(2+)-ATPase was investigated by Fourier transform infrared (FTIR) spectroscopy using the photolytic release of Ca2+ from the photolabile Ca2+ chelator 1-(2-nitro-4,5-dimethoxy)-N,N,N',N',- tetrakis[(oxycarbonyl)]methyl-1,2-ethandiamine (DM-nitrophen). IR absorbance changes in 1H2O and 2H2O were detected in the spectral region from 1800 cm-1 to 1200 cm-1, reflecting photolysis of DM-nitrophen and Ca2+ binding to the Ca(2+)-ATPase. As an independent probe for protein conformational changes, intrinsic fluorescence changes upon Ca2+ release were monitored simultaneously to the FTIR measurements. Both the IR absorbance changes and the fluorescence intensity changes correlated well with the Ca2+ binding activity of the ATPase in this specific step. Ca2+ binding caused IR difference bands mainly in the region of amide I absorption of the polypeptide backbone, reflecting conformational changes of the protein. The small amplitude of the signals indicates that only a few residues perform local structural changes such as changes of bond angles or hydrogen bonding. Other absorbance changes appearing above 1700 cm-1 can be assigned to Ca2+ binding to Glu or Asp side chain carboxyl groups and concomitant deprotonation of these residues. This assignment is strengthened by downshifts of these bands by 4 cm-1 to 6 cm-1 upon 1H2O/2H2O exchange. This is in line with results of mutagenesis studies where such residues containing carboxyl groups were associated with the high affinity Ca2+ binding site (Clarke, D.M., Loo, T.W. and MacLennan, D.H. (1990) J. Biol. Chem. 265, 6262-6267).

Animals↗

PubMed1994

[Current aspects in the treatment of malignant melanoma].

The incidence of melanoma continues to increase throughout the world. Caucasians with particular phenotypic features seem to be affected most. Epidemiologic studies suggest that intermittent sun exposure, especially in early age, increases the risk of melanoma. If melanoma is diagnosed early and treated with adequate surgery, prognosis is excellent. Once melanoma has metastasized to the regional lymph nodes, the majority of patients have a recurrence within 5 years. Adjuvant modalities, currently being tested in many phase III studies, are designed to improve survival of these patients. Isolated limb perfusion with tumor necrosis factor induces complete responses in the majority of patients with in-transit disease. Median survival of patients with distant metastasis is only 6-8 months, and thus far systemic therapy has not significantly prolonged survival, despite remission rates of 30-50%.

Chemotherapy, Adjuvant↗

PubMed1994

Changes of protein structure, nucleotide microenvironment, and Ca(2+)-binding states in the catalytic cycle of sarcoplasmic reticulum Ca(2+)-ATPase: investigation of nucleotide binding, phosphorylation and phosphoenzyme conversion by FTIR difference spectroscopy.

Changes of infrared absorbance of sarcoplasmic reticulum Ca(2+)-ATPase (EC 3.6.1.38) associated with partial reactions of its catalytic cycle were investigated in the region from 1800 to 950 cm-1 in H2O and 2H2O. Starting from Ca2E1, 3 reaction steps were induced in the infrared cuvette via photolytic release of ATP and ADP: (a) nucleotide binding, (b) formation of the ADP-sensitive phosphoenzyme (Ca2E1P) and (c) formation of the ADP-insensitive phosphoenzyme (E2P). All reaction steps caused distinct changes of the infrared spectrum which were characteristic for each reaction step but comparable for all steps in the number and magnitude of the changes. Most pronounced were absorbance changes in the amide I spectral region sensitive to protein secondary structure. However, they were small--less than 1% of the total protein absorbance--indicating that the reaction steps are associated with small and local conformational changes of the polypeptide backbone instead of a large conformational rearrangement. Especially, there is no outstanding conformational change associated with the phosphoenzyme conversion Ca2E1P-->E2P. ADP-binding induces conformational changes in the ATPase polypeptide backbone with alpha-helical structures and presumably beta-sheet or beta-turn structures involved. Phosphorylation is accompanied by the appearance of a keto group vibration that can tentatively be assigned to the phosphorylated residue Asp351. Phosphoenzyme conversion and Ca(2+)-release produce difference signals which can be explained by the release of Ca2+ from carboxylate groups and a change of hydrogen bonding or protonation state of carboxyl groups.

Adenosine Diphosphate↗

PubMed1994

Polyvalent melanoma cell vaccine induces delayed-type hypersensitivity and in vitro cellular immune response.

Patients with melanoma metastatic to distant sites or at high risk for recurrent melanoma have been treated with a polyvalent melanoma cell vaccine (MCV) in phase II protocols. We assessed in vivo and in vitro cell-mediated responses to MCV in 163 patients who had undergone surgical resection of American Joint Committee on Cancer stage III melanoma. During the first 4 months of vaccine immunotherapy, 135 patients (83%) responded by developing a positive delayed-type hypersensitivity reaction > or = 6 mm to MCV. In a mixed lymphocyte tumor cell reaction using peripheral blood lymphocytes, 35 of 42 patients (83%) showed a recall proliferative response to one or more of the three cell lines of MCV. There was a significant correlation between delayed-type hypersensitivity reaction and mixed lymphocyte tumor cell reaction (P = 0.013). After 4 months of MCV therapy, 8 of 11 patients had an increased mixed lymphocyte tumor cell reaction to autologous melanoma cells. During the first 4 months of vaccine therapy, 16 of 33 patients developed more than a 50% increase in cytotoxic T-cell activity against one of the cell lines of MCV. Overall survival was significantly prolonged in patients with a positive delayed-type hypersensitivity reaction (P = 0.0054) and/or increased cytotoxic T-cell activity (P = 0.02). These findings suggest that MCV induces specific T-cell responses which are correlated with clinical course; the data also suggest that some of these responses are directed against autologous melanomas and may play a major role in controlling the progression of melanoma.

Adolescent↗

PubMed1994

[Treatment of severe idiopathic cold-agglutinin diseases using interferon-alpha 2b].

Cold agglutinin disease is an immunohemolytic anemia in which the autoantibody directly agglutinates human red blood cells below body temperature, maximally at 0 to 5 degrees C. The disease is considered to occur in primary (idiopathic) or secondary forms. The secondary form is noticed in the setting of infections (e.g. Mycoplasma pneumoniae, infectious mononucleosis), or patients with lymphoproliferative disorders. Affected patients show varying clinical presentation ranging from mild to serious hemolytic anemia, episodic hemoglobinuria, acrocyanosis, or other peripheral vaso-occlusive events which are all occasioned by cold exposure. In mild chronic cold agglutinin disease preventing cold exposure usually suffices to avoid disease exacerbation. However, treatment of severe disease is difficult. Splenectomy or glucocorticoids are generally disappointing, but exceptions have been reported. Treatment with alkylating agents, as for example chlorambucil or cyclophosphamide, may be effective in some patients. However, late effects, and in particular their carcinogenic potential when used as long-term treatment, must be born in mind. We report on a 59-year-old woman with severe cold agglutinin disease who was at first treated successfully with chlorambucil and prednisone. Based on in vitro evidence, primary cold agglutinin disease can be considered as a low grade malignant lymphoproliferative disorder in which interferon-alpha has been shown to be an effective therapeutic agent, at least in forms such as hairy cell leukemia. We therefore switched therapy to interferon-alpha 2b (three million units/m2 body surface area subcutaneously three times weekly). 18 months after treatment initiation there was no remission, but improvement of clinical and laboratory signs of the disease was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Hemolytic, Autoimmune↗

PubMed1994

Characterization and augmentation of CD4+ cytotoxic T cell lines against melanoma.

Cytotoxic T cells have been implicated in the control of the progression of human melanoma. Most studies on human tumor T cell immunity have focused on the CD3+CD8+ cytotoxic T lymphocyte (CTL) phenotype; however, CD3+CD4+ CTL are important effector cells in other diseases and may also contribute to antimelanoma immunity. In this study we compared the functional activity of CD3+CD4+ and CD3+CD8+ CTL lines generated against autologous melanoma cells. CD8+ CTL had twofold higher cytotoxicity and serine esterase activity than CD4+ CTL. CD8+ CTL also were better binders to autologous melanoma cells. Binding of both CD4+ and CD8+ CTL to melanoma cells was significantly inhibited by ICAM-1 mAb. Interleukin-2 (IL-2) and IL-4 secretion was induced in both CD4+ and CD8+ CTL after stimulation by melanoma cells. A reverse transcriptase polymerase chain reaction performed on specific messenger RNA showed that both CD4+ and CD8+ CTL expressed IL-1, IL-2 and IL-4; CD4+ CTL also expressed interferon gamma (IFN). Both CTL phenotypes expressed receptors for IL-2 and IFN but only CD4+ CTL expressed the receptor for IL-4. Methods to augment CD4+ CTL growth were assessed using different combinations of cytokines. The combination of IL-2, IL-4 and IFN provided the optimal stimulation. Treatment of melanoma target cells with IL-4 and IFN enhanced CD4+ CTL recognition activity. CD4+ T cells are associated with antigen memory response and helper function, therefore activation of CD4+ CTL may be more beneficial with respect to long-term protective antimelanoma immunity.

Base Sequence↗