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M Haber

Publications and source records attributed to M Haber.

At least 55 records · Page 3Linked to original sources
PubMed1999

Safety profile of Lansoprazole: the US clinical trial experience.

OBJECTIVE: Lansoprazole has undergone extensive clinical evaluation for the treatment of acid-peptic diseases. The aim of this study was to define the safety profile of lansoprazole and compare it to that of other therapeutic agents evaluated in the same controlled trials. METHODS: The clinical safety profile of lansoprazole and comparative agents (placebo, ranitidine and omeprazole) was reviewed for 3281 patients who participated in short term (up to 8 weeks) and long term (up to 56 months) clinical trials conducted in the US. Adverse events, laboratory value changes and gastric biopsy changes that occurred during treatment were compared statistically for differences between treatments. RESULTS: The incidence of adverse events and number of patients discontinuing treatment because of adverse events was similar for lansoprazole and comparative agents. Other than elevated serum gastrin levels, a known effect of proton pump inhibitors, no trends in laboratory changes were observed. Median values for gastrin levels remained within the normal range; about 2% of patients had gastrin levels >400 pg/ml at any time, while <1% had 2 or more gastrin values >500 pg/ml. Values returned to baseline levels after therapy was discontinued. No significant changes in gastric endocrine cell growth from baseline to final visit were observed, nor was there evidence of dysplasia or neoplasia. CONCLUSION: Lansoprazole is well tolerated for both short and long term treatment of acid-related disease. The tolerability of lansoprazole is comparable to that of ranitidine, omeprazole and placebo in the treatment of these diseases.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

Helicobacter heilmannii gastritis: association with acid peptic diseases and comparison with Helicobacter pylori gastritis.

We analyzed 2 antral and 1 corpus full-thickness random endoscopic gastric mucosal samples obtained from 946 patients with duodenal ulcers (6077 biopsies) and from 281 patients with nonsteroidal anti-inflammatory drug-associated gastric ulcers (1794 biopsies). We stained tissue sections with hematoxylin and eosin and Warthin-Starry silver stain and immunostained them with polyclonal antibodies against Helicobacter pylori. Hematoxylin- and eosin-stained sections from 6 patients with Helicobacter heilmannii (18 biopsies) and 23 randomly selected patients with H. pylori (68 biopsies) were evaluated and semiquantitated for the presence of acute inflammation, chronic inflammation, glandular atrophy, intestinal metaplasia, H. pylori, H. heilmannii, lymphoid follicles, or vasodilatation. Additional specimens were obtained for H. pylori culture, a CLO test, and serologic examination. H. heilmannii was detected in 6 (0.49%) of 1227 patients (14 [0.18%] of 7871 biopsies). Of these, 4 (0.42%) of 946 were patients with duodenal ulcers (9 [0.15%] of 6077 biopsies), and 2 (0.71%) of 281 were patients with nonsteroidal anti-inflammatory drug-associated gastric ulcers (5 [0.28%] of 1794 biopsies). We found H. heilmannii with hematoxylin and eosin stain, Warthin-Starry stain, and immunoperoxidase stain for H. pylori. Culture for H. pylori was negative in the four patients with duodenal ulcers. The CLO and serologic tests were positive in three of five and five of five patients, respectively. Our results indicate that H. heilmannii, like H. pylori, is associated with peptic ulcer disease (both active and inactive gastritis) and that it preferentially colonizes the gastric antrum. The severity of the H. heilmannii-associated gastritis is less intense and lymphoid aggregates are less common than in H. pylori-associated gastritis. Morphologic detection seems to be the method of choice for detecting H. heilmanni. Immunoperoxidase stain specific for H. pylori also stains H. heilmannii, indicating cross-reacting antigenic epitopes between H. heilmannii and H. pylori.

Adult↗
PubMed1998

Estimation of individual and population vaccination effectiveness from time-to-event data.

Longini and Halloran and Halloran et al. recently developed a method for estimation of parameters related to the efficacy of a vaccine and to the transmission of an infectious disease from time-to-event (disease or infection) data. This work uses their method to evaluate the individual and population effectiveness of a vaccination programme (Haber et al.). Data from an outbreak of measles in Chad illustrates the new methods.

Evaluation Studies as Topic↗
PubMed1998

P-glycoprotein-mediated methotrexate resistance in CCRF-CEM sublines deficient in methotrexate accumulation due to a point mutation in the reduced folate carrier gene.

We have previously described a series of methotrexate (MTX)-selected CCRF-CEM sublines (CEM/MTX R1-3) displaying increased resistance to drugs associated with the multidrug resistance phenotype and have provided evidence that MDR1 P-glycoprotein contributes to multifactorial MTX resistance in these cells. We have also suggested that P-glycoprotein-mediated MTX transport arises in these cells due to a deficiency in the normal MTX transport route, the reduced folate carrier (RFC). We have now determined the nucleotide sequence of the RFC gene in CEM/MTX R1-3 cells and confirm that the carrier is defective in these cells as a result of a premature stop mutation at codon 99, which severely truncates the encoded protein. CEM/MTX R3 cells were removed from MTX, and a series of sublines with increasing MDR1 expression were derived, following selection with vincristine. These cells show increasing cross-resistance to vincristine as well as other drugs associated with the multidrug resistance phenotype. More importantly, the increased P-glycoprotein expression correlates with increased resistance to MTX, supporting the hypothesis that in cells with a defective carrier protein, MTX can become a substrate for P-glycoprotein. Our data have implications for the P-glycoprotein-mediated transport of other hydrophilic drugs in situations where the relevant carrier protein has been functionally inhibited.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Favorable prognostic significance of high-level retinoic acid receptor beta expression in neuroblastoma mediated by effects on cell cycle regulation.

We have previously shown that ectopic overexpression of retinoic acid receptor (RAR) subtypes alpha, beta and gamma in human neuroblastoma cells had different effects on growth and retinoid sensitivity. Only overexpressed RAR beta induced profound growth inhibition in the absence of additional retinoid, and increased retinoid sensitivity. In this study, we measured mRNA expression levels of RAR alpha, beta, and gamma in 50 primary neuroblastoma tumor samples, and found a strong correlation between favorable patient prognosis and high-level RAR beta expression. Human neuroblastoma cells transfected with a vector expressing RAR beta demonstrated irreversible growth arrest following a 1 week exposure to all-transretinoic acid, whereas control cells continued to proliferate. In the absence of additional retinoid, RAR beta transfectants demonstrated a higher proportion of cells in the G0/G1 phase of the cell cycle, increased p21WAF1/CIP1 expression and specific binding to a retinoic acid response element. These were changes which we also observed in control neuroblastoma cells following retinoid treatment. Our data indicate that RAR beta is an important factor mediating the growth inhibitory effects of retinoids in neuroblastoma cells. The favorable effect of high-level RAR beta expression on prognosis in primary tumor tissue may occur through RAR beta effects on p21 expression and consequent G0/G1 cell cycle arrest.

Cell Cycle↗
PubMed1998

Absence of MEN2A- or 2B-type RET mutations in primary neuroblastoma tumour tissue.

Specific germline mutations in the RET proto-oncogene predispose to the familial cancer syndromes: multiple endocrine neoplasia (MEN) types 2A and 2B, and familial medullary thyroid carcinoma. Expression of the RET receptor tyrosine kinase is tightly restricted to tumours of neural crest origin, such as neuroblastoma, and neuroblastoma has been observed in RET transgenic mice. Neuroblastoma tumour cell lines transfected with the MEN2A RET gene exhibit spontaneous neuritic differentiation, whereas MEN2B-type RET transfectants demonstrate altered cell adhesion and enhanced metastatic potential. In this study, the authors examined genomic DNA from 26 primary neuroblastoma tumours for MEN2A and MEN2B RET mutations, using restriction enzyme digestion of polymerase chain reaction products as an alternative to direct sequencing. Examination of RET exons 10 (codons 611, 618, 620), 11 (codons 632, 633, 634) and 16 (codon 918) in all 26 tumours revealed no RET mutations. Taken together these data suggest that abnormalities of the RET signalling pathway, rather than oncogenic, MEN2-type RET activation by mutation, may play a role in neuroblastoma tumorigenesis.

DNA, Neoplasm↗
PubMed1998

Double-blind comparison of lansoprazole 15 mg, lansoprazole 30 mg, and placebo in the maintenance of healed gastric ulcer.

Our purpose was to compare the safety and efficacy of lansoprazole 15 mg and 30 mg with placebo in preventing recurrence in 49 patients with a history of gastric ulcer. Within one month, 40% of patients receiving placebo experienced ulcer recurrence compared to 0% and 7% of patients receiving lansoprazole 15 mg and 30 mg, respectively. All placebo patients became symptomatic, experienced ulcer recurrence or withdrew from the study by month 9. As compared to placebo, a significantly (P < 0.001) higher percentage of patients treated with lansoprazole 15 mg (83%) and lansoprazole 30 mg (93%) with healed gastric ulcer disease remained healed at month 12. Of patients asymptomatic at baseline, 100% and 59% of those treated with lansoprazole 15 mg and 30 mg, respectively, remained asymptomatic at month 12. The incidence of adverse events was comparable among the treatment groups. Lansoprazole safely and effectively reduces ulcer recurrence in patients with a history of gastric ulcer disease.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

[Observations on the pH value of various artificial tears preparations].

BACKGROUND: The pH-values of artificial tears have not been examined up to now. MATERIALS AND METHODS: The pH-values of 20 commercially available artificial tears were determined. RESULTS: pH-values measured from 4.82 to 8.39. One sixth showed pH-values above physiological values. CONCLUSION: A remarkable proportion of commercially available artificial tears deviate from the physiological range of the pH. It does not seem advisable to apply those in eyes with damaged anterior segments.

Germany↗
PubMed1998

Triple versus dual therapy for eradicating Helicobacter pylori and preventing ulcer recurrence: a randomized, double-blind, multicenter study of lansoprazole, clarithromycin, and/or amoxicillin in different dosing regimens.

OBJECTIVE: The efficacy and safety of dual and triple therapies with a proton pump inhibitor and antibiotic(s) for therapy of Helicobacter pylori-associated duodenal ulcer disease have been compared using results from independent studies using different methods and regimens, making interpretation difficult. In a large, double-blind, multicenter study conducted in the United States, we compared a triple therapy regimen with four dual therapy and one monotherapy regimens in the eradication of H. pylori and the prevention of ulcer recurrence. METHODS: Patients with active duodenal ulcer disease or history of duodenal ulcer disease within the past year and H. pylori infection were randomized to receive one of six 14-day treatment regimens: lansoprazole 30 mg, clarithromycin 500 mg, and amoxicillin 1 gm b.i.d.; lansoprazole 30 mg b.id. and either clarithromycin 500 mg b.i.d. or t.i.d.; lansoprazole 30 mg b.i.d. or t.i.d. with amoxicillin 1 gm t.i.d.; or lansoprazole 30 mg t.i.d. alone. No additional acid suppression therapy followed eradication therapy. Primary efficacy endpoints were eradication of H. pylori and ulcer recurrence. RESULTS: Of 396 patients enrolled in the study, 352 met the entry criteria for duodenal ulcer status and H. pylori positivity. At 4-6 wk after the end of therapy, H. pylori was eradicated from 94% (44 of 47) of patients receiving lansoprazole, clarithromycin, and amoxicillin triple therapy, 77% (39 of 51) of those receiving lansoprazole t.i.d./amoxicillin t.i.d., 75% (36 of 48) of those receiving lansoprazole b.i.d./clarithromycin t.i.d., 57% (28 of 49) of those receiving lansoprazole b.i.d./clarithromycin b.i.d., 53% (26 of 49) of those receiving lansoprazole b.i.d./amoxicillin t.i.d., and 2% (1 of 53) of those receiving lansoprazole monotherapy (p < or = 0.05, triple therapy vs each dual therapy and each dual therapy vs monotherapy). Of those patients who were documented as free of ulcer at 4-6 wk after treatment, ulcers recurred within 6 months in 7% of patients receiving triple therapy, as compared with 13-23% of patients receiving dual therapy, and 69% of patients receiving lansoprazole monotherapy. Patients who were H. pylori negative at 4-6 wk after treatment were less likely to have an ulcer recurrence than were patients who were H. pylori positive (11% [10 of 95] vs 47% [20 of 43], respectively, across treatment groups). For triple therapy and dual therapy, a similar proportion of patients reported a drug-related adverse event (23% vs 17-33%, respectively). CONCLUSIONS: In patients with active or a recent history of duodenal ulcer, a 14-day course of lansoprazole-based triple therapy without additional acid suppression therapy is highly effective in the eradication of H. pylori and in preventing ulcer recurrence. Among the dual therapies, higher eradication rates occurred when lansoprazole (with amoxicillin) or clarithromycin (with lansoprazole) was administered t.i.d. vs b.i.d., but the rates were still significantly lower than with lansoprazole triple therapy with all three drugs administered b.i.d.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

Molecular detection of acute lymphoblastic leukaemia in boys with testicular relapse.

AIMS: To determine the role of polymerase chain reaction (PCR) based minimal residual disease (MRD) detection of leukaemia specific DNA in testicular relapse in childhood acute lymphoblastic leukaemia. METHODS: DNA was obtained from archival testicular and bone marrow samples from boys with acute lymphoblastic leukaemia who relapsed in the testes. Overlapping DJH clone specific primers derived from clonal immunoglobulin heavy chain (IgH) gene rearrangement in each case were used to analyse testicular or bone marrow DNA. RESULTS: Histologically normal end of treatment testicular biopsies in the five patients in longterm remission were all MRD negative, but MRD positive in three of six boys with subsequent testicular relapse. Histologically normal bone marrow samples taken at the end of treatment were MRD negative in five of seven cases, but MRD positive in all cases at the time of isolated testicular relapse. Three boys with unilateral testicular relapse underwent unilateral orchidectomy, rather than bilateral testicular irradiation, as part of their treatment. Two of these boys were MRD positive in the histologically uninvolved testes, and both had subsequent relapses either in the testes or the bone marrow, while the MRD negative patient has not had a testicular relapse. CONCLUSIONS: The presence of MRD in testicular tissue can be assayed with a PCR based method to detect clone specific antigen receptor gene rearrangements. In this setting, PCR is more sensitive than conventional testicular histology for predicting clinical outcomes. MRD assays might be useful in the management of boys at the time of isolated testicular relapse, to confirm the presence of unilateral testicular disease.

Bone Marrow↗
PubMed1998

Prognostic significance of MYCN oncogene expression in childhood neuroblastoma.

PURPOSE: To assess the significance of MYCN gene expression as a prognostic factor in patients with neuroblastoma of various ages, and to determine whether it can predict for outcome independently of MYCN gene amplification. PATIENTS AND METHODS: The level of MYCN gene expression in 60 specimens of primary untreated neuroblastoma was determined by reverse-transcriptase polymerase chain reaction (RT-PCR) analysis. RESULTS: High levels of MYCN gene expression were associated with advanced tumor stage (P=.0005), with the presence of MYCN gene amplification (P < .0001), but not with older age at diagnosis. Among patients who lacked MYCN gene amplification, the levels of MYCN gene expression were significantly greater in the tumors of infants compared with those of older children (P < .0005). High MYCN expression was strongly associated with reduced survival and event-free survival in the overall study population (P < .005), and also in the subset of patients aged older than 1 year at diagnosis (P < .001). In contrast, MYCN expression did not appear to be predictive of outcome in infants. After adjustment for the effect of MYCN amplification, high levels of MYCN expression retained significant prognostic value for poor survival (relative hazards, 30.3; P=.003) in children aged older than 12 months at diagnosis. CONCLUSION: High MYCN gene expression is strongly predictive of poor outcome in older children with neuroblastoma, but not in infants. The findings help explain the controversy in the literature about the prognostic value of MYCN gene expression and highlight the different biology of neuroblastoma that presents in infants and older children.

Child↗
PubMed1997

Improved PCR assay for the detection of antigen receptor gene rearrangements.

The detection of small numbers of leukaemia cells in patients with occult disease has important clinical implications. Leukaemia is a monoclonal disease which frequently displays clonal rearrangement of the T-cell receptor gamma (TCR gamma) and/or immunoglobulin heavy chain (IgH) gene. Clone-specific junctional sequences arising as a result of these gene rearrangements provide potentially valuable targets for monitoring residual disease by the polymerase chain reaction (PCR). However, existing strategies for PCR amplification of these clone-specific rearrangements frequently lack the necessary sensitivity or specificity, due either to the small size of the target junctional region, or to interference resulting from polyclonal IgH or TCR gamma rearrangements in normal lymphocytes. We have previously described a novel PCR strategy to overcome these obstacles which is based on the design of two overlapping clone-specific PCR primers which span the junctional region. We now describe a modification to this strategy which employs relatively short clone-specific primers which further increases the level of specificity. This new method should improve the detection of residual cells, particularly in those cases displaying small junctional regions. Unlike other strategies, specificity is generated from the initial round of amplification. This non-radioactive technique should thus prove effective in monitoring residual leukaemia in patients.

Bone Marrow↗
PubMed1997

Expression of multiple endocrine neoplasia 2B RET in neuroblastoma cells alters cell adhesion in vitro, enhances metastatic behavior in vivo, and activates Jun kinase.

Point mutations, deletions, and recombinations of the RET proto-oncogene are associated with several inherited human diseases of neural crest-derived cells: Hirschsprung's disease, familial medullary thyroid carcinoma, and the multiple endocrine neoplasia (MEN) syndromes, types 2A and 2B. RET expression is restricted to normal and malignant cells of neural crest origin, such as human neuroblastoma cells. To better understand the role of the activated RET oncogene in neural crest cells, we transfected two adherent human neuroblastoma tumor cell lines with oncogenic MEN2 mutant RET cDNAs. Transfectant clones from both cell lines overexpressing MEN2B RET demonstrated a marked increase in the cell fraction growing in suspension. Both control and MEN2B cells formed tumors at the site of injection in all cases. However, mice injected with MEN2B cells developed lung metastases at a much higher frequency than control mice. Only RET protein derived from MEN2A transfectant cells had increased autokinase activity, whereas MEN2B transfectant cells demonstrated selective activation of the mitogen-activated protein kinase, Jun kinase-1 (Jnk1). These results indicate a biochemical signaling pathway that may link oncogenic RET with the metastatic process.

Amino Acid Substitution↗
PubMed1997

Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes.

The treatment of advanced ovarian cancer with taxol is hindered by the development of drug resistance. The cellular target for taxol is the microtubule that is stabilized by the drug. Taxol preferentially binds to the beta subunit of tubulin of which there are six distinct isotypes in mammalian cells. We have used highly specific oligonucleotides and polymerase chain reaction to analyze expression of all six beta-tubulin genes. Human lung cancer cells (A549) were selected in 12 and 24 nM taxol resulting in cell lines that were 9- and 17-fold resistant, respectively. These cells displayed an altered ratio of classes I, II, III, and IVa beta-tubulin isotypes. Ovarian tumors, seven untreated primary and four taxol- resistant tumor-bearing ascites, displayed significant increases (P < 0.005) in classes I (3.6-fold), III (4.4-fold), and IVa (7.6-fold) isotypes in the taxol-resistant samples as compared with untreated primary ovarian tumors. The increased expression appears to be related to the resistance phenotype, as the basal levels of the class III and IVa isotypes in the untreated tumors were extremely low. This is the first report of altered expression of specific beta-tubulin genes in taxol-resistant ovarian tumors and we propose that the latter may play a role in clinical resistance to taxol.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Estimation of the population effectiveness of vaccination.

This paper presents a simple method for estimation of population vaccination effectiveness, which is the fraction of disease cases prevented by a vaccination programme. The method is based on the susceptible-infectious-recovered (SIR) model for the spread of an epidemic in a heterogeneous population under non-homogeneous mixing. The required data are the attack rates among vaccinated and unvaccinated individuals in each stratum of the population. Some information on the mixing pattern may be useful, but in most cases is not absolutely necessary. One can extend the estimation method to predict the attack rates expected in the same population for different vaccination strategies. I apply the new methods to data from a measles outbreak and investigate the bias, standard error and robustness of the estimation method in a stochastic simulation study.

Bias↗
PubMed1997

The prognostic value of MDR1 gene expression in primary untreated neuroblastoma.

The contribution of MDR1 gene expression to the biology of childhood neuroblastoma is unclear. To clarify the role of MDR1 in this malignancy, we examined the relationship between MDR1 expression and patient outcome in subsets of 60 primary untreated neuroblastomas for which MYCN gene copy number and expression of the multidrug resistance-associated-protein (MRP) gene had been previously characterised. In contrast to MRP gene expression, MDR1 expression was lower in tumours with MYCN gene amplification compared with those without amplification. Strong correlations between MDR1 and MRP gene expression, and between MDR1 and MYCN gene expression, were observed in tumours lacking MYCN gene amplification (P < 0.0005). In these single-copy tumours, very high MDR1 gene expression was significantly associated with poor outcome (P < 0.05). Very high MDR1 expression was also strongly predictive of poor outcome in older children (P < 0.0001), but not in infants. These findings suggest a clinical role for the MDR1 gene in specific subgroups of primary neuroblastoma.

ATP-Binding Cassette Transporters↗
PubMed1997

Evidence that the MYCN oncogene regulates MRP gene expression in neuroblastoma.

We have recently shown that expression of the multidrug resistance-associated protein (MRP) gene is a powerful prognostic indicator in childhood neuroblastoma and have suggested that the MYCN oncogene may regulate MRP gene expression. To address this hypothesis, we have examined the relationship between MYCN and MRP gene expression in neuroblastoma tumours and cell lines. MYCN and MRP gene expression were highly correlated in 60 primary untreated tumours both with (P = 0.01) and without MYCN gene amplification (P < 0.0001). Like MRP, high MYCN gene expression was significantly associated with reduced survival, both in the overall study population and in older children without MYCN gene amplification (relative hazards = 13.33 and 19.61, respectively). Inhibition of MYCN, through the introduction of MYCN antisense RNA constructs into human neuroblastoma cells in vitro, resulted in decreased MRP gene expression, determined both by RNA-PCR and Western analysis. The data are consistent with MYCN influencing neuroblastoma outcome by regulating MRP gene expression.

Age Factors↗