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Biomedical subjects

B Stark

Publications and source records attributed to B Stark.

At least 19 recordsLinked to original sources
PubMed2006

Low efficacy of methotrexate in childhood acute myeloid leukemia (AML): single-agent therapeutic window study in relapsed AML.

BACKGROUND: The efficacy in pediatric acute myeloid leukemia (AML) of single-agent methotrexate (MTX) at a higher dose than previously applied, 1,000 mg/m2, given as a theoretically beneficial 36-hr continuous infusion, is unknown, but may be beneficial based on preclinical data. PROCEDURE: We performed a therapeutic window study in children with first relapsed AML treated in four different countries. RESULTS: Based on a comparison between the percentage of leukemic blasts in the bone marrow shortly before and 7-10 days after the MTX infusion, none of the first cohort of nine patients showed a good response, defined as a reduction of blasts of at least 50%. Therefore, the study was closed, concluding that the probability of a good response in this patient-group was most likely to be less than 30%. By that time, another four patients had been enrolled, of which one patient with a late relapsed AML FAB type M7 showed a good response. Toxicity of MTX was limited and tolerable. CONCLUSIONS: This study shows that single-agent MTX in the applied regimen in pediatric relapsed AML has limited efficacy. However, it also demonstrates the feasibility of an international and therapeutic window phase II study in pediatric relapsed AML.

Adolescent↗
PubMed2004

Molecular variants of the ATM gene in Hodgkin's disease in children.

Ataxia telangiectasia is an autosomal recessive disease with a striking predisposition of lymphoid malignancies. ATM mutations have been reported in adult sporadic lymphoma and leukaemia. The aim of this study was to investigate the possible involvement of the ATM gene in the carcinogenesis of Hodgkin disease in children. Tumours were obtained from 23 patients and were subjected to mutation screening and loss of heterozygosity analysis. Eight base substitutions were identified in seven patients. Of them, Y54Y, a silent change, was observed in two patients and a known polymorphism, D1853N, in three patients. Of the other two patients, one harboured a combined genotype P604S/F1463C, identified previously in two patients with Hodgkin lymphoma, and the other a novel missense mutation, V595A. The alterations were present in the germ line, and both had a more aggressive disease. In all, 100 matched normal ethnic controls were screened for these mutations and P604S/F1463C was identified in one healthy control. Loss of heterozygosity was identified in four patients and in three of them it was located centromeric to the ATM gene, and, in one, it spanned a large region, indicating the involvement of other tumour-suppressor genes in this disease. Missense variants of the ATM gene are a rare event in childhood Hodgkin disease.

Adolescent↗
PubMed2001

Distribution of TGF-beta, the TGF-beta type I receptor and the R-II receptor in peripheral nerves and mechanoreceptors; observations on changes after traumatic injury.

The mechanisms governing the regeneration of denervated peripheral mechanoreceptors are similar to those of peripheral nerves. The ability to regenerate depends partly on changes of the Schwann cell phenotype. The transforming growth factor beta (TGF-beta) family have been implicated in induction of Schwann cell proliferation, production of extracellular matrix and neurotrophin synthesis as well as synthesis or repression of cell adhesion molecules. Hence, they may prove to be of importance for regenerative mechanisms in peripheral mechanoreceptors. The distribution of TGF-beta, the receptors I and II and intra-cellular second messengers, Smad 2/3 and 4 was assessed in sensory neurones, peripheral nerves and mechanoreceptors by immuno-histochemistry, immuno-electron microscopy and in situ hybridisation. TGF-beta2 mRNA and TGF-beta2-like immunoreactivity (IR) were expressed in injured small and medium sized rat sensory neurones of dorsal root ganglia. TGF-beta and receptor II mRNA and immunoreactivities (IR) were present in satellite cells. Intact and injured sensory neurones expressed receptor I mRNA and Smad 2 mRNA. TGF-beta2 mRNA was found in transected nerve stumps and in sensory mechanoreceptors. TGF-beta1, 2 and Smad 4 were also observed in inner core lamellar cells of intact and denervated cat Pacinian corpuscles. Lamellar cells of intact and denervated Meissner corpuscles were TGF-beta immunoreactive. Merkel cells were receptors I and II immunoreactive. In conclusion, cutaneous and subcutaneous mechanoreceptors differ with regard to the expression of TGF-beta isoforms and receptors.

Activin Receptors, Type I↗
PubMed2001

Near haploid childhood acute lymphoblastic leukemia masked by hyperdiploid line: detection by fluorescence in situ hybridization.

Near-haploid (<30 chromosomes) acute lymphoblastic leukemia (ALL) is a rare and unique subgroup of childhood common ALL associated with a very poor outcome. It may be underdiagnosed when masked by a co-existing hyperdiploid line, which has to be distinguished from the common good-prognostic hyperdiploid (>50 chromosomes) ALL. We present three children in whom, by conventional cytogenetics, near-haploid ALL was detected on relapse. Using interphase FISH probes of chromosomes X, Y, 4, 12, and 21, we were able, in two cases, to trace the hidden near-haploid lines of approximately 5% and 20% of the cells, masked by hyperdiploid cells of approximately 80% and 70%, respectively; at relapse, the proportion was reversed, with predominant near-haploid lines of over 80% and residual hyperdiploidy of less than 10%. The near-haploid lines consisted of 24 and 27 chromosomes, and always retained the second copy of chromosome 21 or its derivative, as detected in one of our patients by SKY. The hyperdiploid clones were the exact duplicates of the near-haploid ones and contained four and two copies of the chromosomes represented in two and one copies in the near-haploid stem line, respectively. Unlike the common hyperdiploid ALL, no trisomies were observed. The patients were all aged >10 years, with WBC 0.7-30 x 10(9)/L, and a common ALL phenotype. They were treated with the ALL-BFM-95 protocol, medium risk group, and responded well to 8 days of steroid therapy, but relapsed early, within 11 months, and died a few months later. Interphase FISH technique is recommended for the detection of cryptic near-haploid clones in the diagnostic survey of ALL. To assess the prognostic value of near-haploidy in the context of the ALL-BFM protocols, a larger cohort of patients is required.

Adolescent↗
PubMed2001

Distribution of the neurotrophin receptors p75 and trkB in peripheral mechanoreceptors; observations on changes after injury.

The neurotrophin family mediates effects of growth, cell differentiation and cell death through low- and high-affinity transmembrane receptors. The Pacinian corpuscle (PC) is the largest peripheral mechanoreceptor in mammals and was studied by immuno-histochemistry and immuno-electron microscopy with regard to the distribution of neurotrophin receptors, p75; p140 trkA, p145 trkB and 145 trkC. TrkA- and trkC-like immunoreactivity (IR) was not expressed in rat and cat PCs. Developing and adult animals expressed p75 and trkB in lamellar cells of the PC. The inner core cells, thought to be specialised Schwann cells, demonstrated an injury-induced increased immuno-labelling for trk B. Perineurial-derived outer core cells were reactive to p75 after injury similar to the perineurium of distal nerve stumps. Inner core cells of PCs behaved as leptomeningeal cells with regard to trkB. Outer core lamellar cells of PCs behaved as perineurial cells with regard to p75. A role for brain-derived neurotrophic factor is proposed in the development and nerve regeneration of PCs via an anterograde messenger transfer through p75 and trkB.

Animals↗
PubMed2001

Dermal fibroblasts genetically engineered to release nerve growth factor.

Current surgical strategies for repair of critical nerves involves the transfer of normal donor nerve from an uninjured body location. One possible alternative to autogenous tissue replacement is the development of engineered constructs to replace those elements necessary for axonal proliferation. Delivery of growth factors is one strategy to enhance synthetic nerve constructs. Thus, this study focused on the delivery of nerve growth factor (NGF) by genetic engineering to begin approaching the microenvironment dictated, in part, by Schwann's cells. Rat dermal fibroblasts (DFBs) were modified genetically to release rat NGF. The reporter gene LacZ was used to assess the optimum nonviral transfection method commercially available before NGF transfection. FuGENE6 provided the optimum transfection efficiency (24% maximum, 20.1 +/- 1.9% 5-day average) as measured by beta-galactosidase catalytic activity. NGF release from transfected DFBs was assessed over a 3-day period. Compared with control (no transfection) DFBs and DFBs transfected with vector alone, DFBs transfected with an expression vector encoding rat beta-NGF demonstrated significantly (p < 0.05) higher levels of NGF, with a 3-day maximum of 111 pg NGF per milliliter. When normalized to cell number, NGF-transfected DFBs released 1.2 pg NGF per milliliter/10(3) cells. The NGF-transfected DFBs demonstrated a maximal NGF release rate at day 1 (1.2 ng NGF/10(6) cells per day), followed by a markedly lower, sustained release rate at days 2 and 3 (0.44 ng NGF/10(6) cells per day and 0.48 ng NGF/10(6) cells per day respectively). The release rate curves for control and vector-transfected DFBs also exhibited a maximal NGF release rate at day 1, but were followed by a decreasing release rate, potentially representing in vitro degradation of NGF present in fetal bovine serum. Although not first with the development of growth factor delivery through fibroblasts, these findings suggest that rat DFBs can be modified genetically to act like Schwann's cells to deliver NGF.

Animals↗
PubMed2001

Perceptions about advance directives by nurses in a community hospital.

Despite the legal mandate for hospitals to comply with the Patient Self-Determination Act and recommendations by the American Nurses' Association for nurses to advocate for the participation of patients in end-of-life decisions, nurses' compliance has been less than enthusiastic. This study used an exploratory descriptive design and a 10-item self-reported questionnaire, which included both multiple-choice and open-ended questions. This study examined nurses' knowledge and comfort with the implementation of the Patient Self-Determination Act. An analysis of this research shows that two major themes emerged: a need for more education involving advance directives and a desire to have other healthcare workers involved in informing patients about advance directives.

Adult↗
PubMed2000

Apparently unrelated clones shown by spectral karyotyping to represent clonal evolution of cryptic t(10;11)(p13;q23) in a patient with acute monoblastic leukemia.

The accurate genetic classification of acute leukemia is of the utmost clinical importance for treatment stratification. In the present study, we report on a young girl with aggressive acute monoblastic leukemia (AML) (M5b) with skin, lymph node, and bone marrow involvement, in whom cytogenetic analysis revealed three clones with different secondary chromosomal changes. Two clones had the secondary +8 and del(9q) aberrations, with the der(11)t(1;11) in the second one; the third clone was apparently unrelated to the others, and had add(7)(p?21),-13,+22. Using the spectral karyotyping (SKY) technique, we found that all three clones originated from a common clone that harbored the hidden primary t(10;11)(p13;q23) or its derivatives, suggesting clonal evolution. The first clone had the balanced t(10;11), the second had its derivative, der(10)t(10;11), and the third had the other derivative, der(11)t(10;11). On fluorescence in situ hybridization (FISH), MLL gene splitting, with translocation of its centromeric portion to 10p, and deletion of its telomeric portion, was demonstrated. In conclusion, the detection of the very poor prognostic t(10;11) aberration in AML, was possible by complementing the traditional cytogenetic analysis with SKY and FISH.

Bone Marrow Cells↗
PubMed2000

Effective preventive central nervous system therapy with extended triple intrathecal therapy and the modified ALL-BFM 86 chemotherapy program in an enlarged non-high risk group of children and adolescents with non-B-cell acute lymphoblastic leukemia: the Israel National Study report.

BACKGROUND: Preventive cranial radiotherapy (CRT) in childhood acute lymphoblastic leukemia (ALL), although effective, may be associated with neurologic sequelae and second malignancies. Attempts to replace CRT with intensified intrathecal therapy (IT) have shown promise in lower risk subgroups. In the Israel National Study (INS) 89 trial, the efficacy of extended triple IT (TIT) alone for cranial prophylaxis in an enlarged non-high risk group (Non-HRG) was assessed in the context of a modified ALL-Berlin-Frankfurt-Munster (BFM) systemic chemotherapy program. METHODS: Non-HRG patients included the standard-risk group (SRG) and the risk group (RG), as defined in ALL-BFM 86. In the INS 89 protocol, all Non-HRG patients were treated with extended TIT x 18 times and systemic therapy based on the BFM 86 protocol, with the addition of etoposide x 4 times. The HRG patients, classified according to BFM 86 criteria, were treated with the BFM 90 HRG protocol including CRT. RESULTS: A total of 250 patients were enrolled. At a median follow-up of 58 months (range, 2-8.5 years), the overall 5-year event free survival (EFS) was 73.5% +/- 3% (standard error ¿SE), and the cumulative central nervous system (CNS) recurrence rate was 4.3% +/- 1.4% (SE) (isolated, 2.3%; combined, 2%). Of the 220 eligible children, 189 (86%) were in the Non-HRG group, and their 5-year EFS was 77.8% +/- 3% (SE). The cumulative CNS recurrence rate for patients without CNS disease at presentation was 3.1% +/- 1% (SE) (isolated, 1.7%; combined, 1.4%). Within the risk subsets defined by the BFM 86 of the Non-HRG, the 5-year EFS rates of the RG (148 patients) and the SRG (41 patients) were 74.8% +/- 4% (SE) and 89.5% +/- 5% (SE), respectively, and the rates of CNS recurrence (isolated and combined) were 4% and 0%, respectively. For the HRG (31 patients), the 5-year EFS and CNS recurrence rates were 47.9% +/- 9% (SE) and 8. 5% +/- 6% (SE), respectively. CONCLUSIONS: Early extended TIT therapy in the context of modified BFM 86 systemic chemotherapy was found to provide adequate CNS protection and systemic leukemia control in patients with non-high risk ALL. However, no benefit for etoposide could be proven in this study.

Antimetabolites, Antineoplastic↗
PubMed2000

Improved outcome in childhood B-cell lymphoma with the intensified French LMB protocol.

BACKGROUND: During the last 20 years, 120 children with B cell lymphoma were treated at the National Pediatric Hematology/Oncology Center of Israel. Until 1986, 63 patients received an institutional protocol (BMC), and thereafter 57 patients received a modified French LMB protocol. We report the results of a retrospective analysis comparing the results of these two protocols. PROCEDURE: Patient characteristics were similar in both groups except for stage of disease and lactate dehydrogenase (LDH) levels. Significantly more patients in the LMB group had higher stage disease, and the LDH levels also were higher (<600 microg/ml). RESULTS: Fifty-four of fifty-seven children on the modified LMB protocol are alive, disease-free, with an overall event-free survival of 94% (median follow-up of 73 months). Event-free survival for stages I, II, and III patients is 100%, and for stage IV 77%, whereas the overall event-free survival was 58% among 63 children treated previously, and for stage IV patients only 10%. Severe marrow suppression and neutropenic enterocolitis were the major complications of this intensive protocol. CONCLUSIONS: Intensive chemotherapy with a modified LMB protocol and modern supportive care result in a high cure rate of childhood B cell lymphoma even in patients with advanced disease.

Adolescent↗
PubMed2000

Developmental and lesion-induced changes in the distribution of the glucose transporter Glut-1 in the central and peripheral nervous system.

The active transport of D-glucose from the vascular to the neural compartment requires the presence of a carrier molecule at the blood-brain and the blood-nerve barrier. The glucose transporter 1 (Glut-1) seems to be the main carrier in blood-tissue barriers of endothelial and perineurial type. The distribution of Glut-1 was assessed in the normal central and peripheral nervous system of young and adult animals and compared with changes after nerve injury. Immuno-histochemistry, in situ hybridization, and perfusions with Evans Blue were carried out. Glut- I was not expressed in the perineurium of peripheral nerves at birth, but appeared in the perineurium of peripheral nerves, spinal roots, in the capsule of dorsal-root ganglia, and in the pia mater of adult animals. The perineurium of peripheral nerves subjected to Wallerian degeneration presented a faint Glut-1 immunoreaction, which was restored after regeneration. Glut-1 was expressed in capillaries of the gray substance of the spinal cord. Perineurial-derived lamellar cells of Pacinian corpuscles exhibited a strong Glut-1-like immunoreactivity in response to denervation and during development. Merkel cells and Meissner corpuscles were found to be Glut-1 negative. Glut-1 seems to reflect the quality of an adult, mature perineurial and blood-nerve barrier.

Adult↗
PubMed2000

Combined intraoperative laparoscopic cholecystectomy and endoscopic retrograde cholangiopancreatography: lessons from 29 cases.

BACKGROUND: The role and timing of endoscopic retrograde cholangiopancreatography (ERCP) in patients with suspected choledocholethiasis remains a controversial subject. There have been few studies exploring the role of intraoperative ERCP. Therefore, we set out to perform a retrospective review of 29 patients who underwent combined laparoscopic cholecystectomy (LC) and intraoperative ERCP (LC/ERCP). Our objective was to assess the feasibility of a one-stage approach using intraoperative ERCP. METHODS: We identified 29 patients in whom LC/ERCP was attempted between January 1996 and November 1998 at a university-affiliated hospital with a large private faculty. Parameters reviewed included preoperative diagnosis, liver function tests (LFT), finding on transcystic cholangiogram (TCC), ERCP, stone retrieval, failure of ERCP, length of stay, morbidity, and mortality. RESULTS: Twenty-eight of 29 patients (97%) underwent successful combined LC/ERCP. Successful TCC followed by ERCP was performed in 21 of 26 patients (81%). Five TCC were technically unsuccessful; in these patients, ERCP was performed on the basis of preoperative criteria. In three patients, TCC was not attempted. Stones were successfully retrieved from 20 of 21 patients (95%) with abnormal finding on TCC, one of five patients (20%) with failed TCC, and two of three patients (67%) with ERCP but without TCC. Overall morbidity was 14%, comprising two patients with postoperative hyperamylasemia and two with cystic duct leaks. There were no deaths in the group. The mean time for the combined procedure was 173 min (range, 50-290). Mean length of hospitalization was 3.4 days, and mean postoperative stay was 2.2 days. CONCLUSIONS: LC/ERCP can be performed safely. The advantages of the combined procedures include one-stage treatment of cholelithiasis and choledocholithiasis, avoidance of unnecessary preoperative ERCP and their concomitant complications, and elimination of potential return to the operating room when postoperative ERCP is technically impossible.

Adolescent↗
PubMed2000

Methotrexate treatment protocols and the central nervous system: significant cure with significant neurotoxicity.

Methotrexate can influence the central nervous system through several metabolic toxic pathways. These effects can be categorized as immediate, acute to subacute, or chronic neurologic syndromes. The acute to subacute syndrome occurs frequently in acute lymphoblastic leukemia treatment protocols, generally manifesting with focal neurologic signs and changes seen on magnetic resonance imaging and single photon emission computed tomography. While in some patients the neurotoxicity is transient and benign and allows for continuation of chemotherapy, in others it can be quite severe and debilitating, leading to permanent neurologic deficits. The need to modify the treatment protocols when neurotoxicity appears is not fully established. It is also unknown whether the use of sufficient amounts of leucovorin can overcome the toxic effects of the drug.

Adolescent↗
PubMed2000

Cerebellar involvement in Langerhans' cell histiocytosis: a progressive neuropsychiatric disease.

We describe a 21-year-old patient who was being followed since the age of 3(1/2) years for Langerhans' cell histiocytosis. Although previously a bright and gifted student, the patient presented at age 16(1/2) with new-onset cerebellar neurologic signs, obsessive-compulsive disorder, and dementia. Findings on magnetic resonance imaging study of the brain were normal, but brain single photon emission computed tomography with technetium 99m ethylene cysteinate dimer showed markedly decreased cerebellar perfusion. This case is unique for the wide extent of the central nervous system involvement in Langerhans' cell histiocytosis, which has not been reported previously. Although obsessive-compulsive disorder has also been associated with several other cerebellar disorders, it is still unknown whether the cerebellum plays a role in its development. We suggest that in some cases, brain single photon emission computed tomography may be superior to magnetic resonance imaging for demonstrating cerebellar disorder in Langerhans' cell histiocytosis.

Adult↗
PubMed1999

Clustering of Pacinian corpuscle afferent fibres in the human median nerve.

To further study the functional organisation of human peripheral nerves, the intrafascicular arrangement of afferent fibres supplying Pacinian corpuscles (PCs) was explored by percutaneous microneurography using thin-calibre, concentric needle electrodes. In normal adults, 20 PC afferents were identified in 13 recording sites. Low-amplitude (less than 30 microm) vibratory stimuli to the skin were applied with tuning forks oscillating at 128 Hz or 256 Hz and response patterns of individual PC units were studied. In many recording sites, two, sometimes even three, PC afferents with adjacent or overlapping receptive fields in the hand were clustered in the nerve. The observed incidence in the records containing a certain number of PC units was compared with the expected probability calculated according to the hypothesis that all nerve fibres are randomly organised in peripheral nerves. The results suggested that PC afferents are partially segregated in the nerve. In addition, PC afferents were neighbouring on slowly adapting type II (SAII) units and skin sympathetic activity in individual fascicles. SAII units often innervated the same skin area as PC units, but did not respond to vibration. The data provided additional information regarding the functional organisation of the human peripheral nerve and the mechanisms underlying the sense of vibration in man with special regard to population behaviour of neighbouring PC mechanoreceptors.

Adult↗