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Biomedical subjects

D S Snyder

Publications and source records attributed to D S Snyder.

At least 55 records · Page 3Linked to original sources
PubMed1995

High-dose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin's disease: results in 85 patients with analysis of prognostic factors.

Eight-five consecutive patients with relapsed or refractory Hodgkin's disease (HD) underwent high-dose chemotherapy or chemo/radiotherapy followed by autologous bone marrow (ABMT) and/or peripheral blood stem cell (PBSC) transplantation. Two preparative regimens were used. Twenty-two patients (26%) without prior radiation received fractionated total body irradiation (FTBI) 1,200 Gy in combination with high-dose etoposide (VP-16) 60 mg/kg and cyclophosphamide (CTX) 100 mg/kg. Sixty-three patients (74%) with prior radiotherapy received carmustine (BCNU) 450 mg/m2 instead of FTBI. The median age was 32 years (range, 16 to 56). The median number of prior chemotherapy regimens was three (range, 1 to 7). Forty-three patients (51%) received transplants in first relapse or second complete remission (CR), whereas 33 (39%) received transplants after second or subsequent relapse. All relapsed patients, except one, received conventional salvage chemotherapy and/or radiotherapy in an attempt to reduce tumor bulk before transplant. At the time of analysis in April 1994, fifty-seven patients (67%) are alive, including 44 (52%) in continuous CR, with a median follow-up for the surviving patients of 28 months (range, 7 to 66). Thirty patients (35%) relapsed at a median of 9 months (range, 1 to 43). Eleven patients (13%) died of transplant-related complications including veno-occlusive disease of the liver (VOD) in five, acute and late interstitial pneumonitis in three, graft failure in one, cerebral hemorrhage in one, and therapy-induced myelodysplasia (MDS)/acute leukemia in one patient. At a median follow-up of 25 months (range, 0.6 to 66), the cumulative probability of 2-year overall and disease-free survival (DFS) of all 85 patients is 75% (95% confidence interval [CI] 64% to 84%) and 58% (95% CI 47% to 69%), respectively. Three independent prognostic variables were identified by univariate analysis: number of prior chemotherapy regimens, prior radiotherapy, and extranodal disease at ABMT. Multivariate stepwise Cox regression identified the number of prior chemotherapy regimens as the only significant prognostic factor predicting for both relapse and DFS. There were no significant differences in the outcome of the treatment between the two preparative regimens. Our results confirm that high-dose therapy and ABMT is an effective therapy for patients with relapsed or refractory HD. Earlier transplantation is recommended before the development of drug resistance and end organ damage that results from repeated attempts of salvage therapy.

Actuarial Analysis↗
PubMed1994

Marrow transplantation from hepatitis C virus seropositive donors: transmission rate and clinical course.

Bone marrow transplant recipients are at risk for acquiring hepatitis C infection from the donated marrow. Twelve patients who were hepatitis C virus (HCV) RNA-negative pretransplant received marrow from anti-HCV seropositive donors. HCV RNA was present in the sera of seven of these donors. After transplant, serial serum specimens were obtained from all marrow recipients for determination of HCV RNA and aminotransferase levels. All seven recipients of marrow from HCV RNA-positive donors were HCV RNA-positive after marrow infusion; none cleared virus from the serum. All five recipients of marrow from anti-HCV seropositive, HCV RNA-negative donors remained free of HCV RNA in serum up to day 100. Abnormal serum aminotransferases were common in both HCV RNA-negative and HCV RNA-positive marrow recipients. One HCV-infected recipient developed marked elevation in aminotransferases after immunosuppressive drugs were stopped. We conclude that the presence of HCV RNA in the serum of marrow donors is an accurate predictor of HCV infection in marrow recipients. The acute infection was subclinical in all patients. The long-term risk of chronic hepatitis C virus infection in these patients remains to be determined.

Adult↗
PubMed1994

Fractionated total-body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients with chronic myelogenous leukemia in chronic phase.

Ninety-four consecutive patients with chronic myelogenous leukemia in first clinical chronic phase, median age of 34.0 years (range, 6.8 to 52.4 years), with a histocompatible sibling donor, were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation (BMT). The median time from diagnosis to BMT was 7.0 months (range, 2.3 to 72.0 months). Sixty patients were treated before BMT with hydroxyurea alone, four patients with busulfan alone, one patient with interferon alone, and the other 29 patients were treated with various combinations of these drugs. Cumulative probabilities of overall survival, event-free survival, and relapse at 5 years were 73%, 64%, and 14%, respectively. The median follow-up time for surviving patients was 38 months, ranging from 12 to 88 months. By stepwise Cox regression analysis, significant prognostic variables were age at transplant, acute graft-versus-host disease > or = grade II, cytomegalovirus-associated interstitial pneumonitis, and years from diagnosis to BMT.

Adolescent↗
PubMed1994

High-dose therapy followed by autologous peripheral-blood stem-cell transplantation for patients with Hodgkin's disease and non-Hodgkin's lymphoma using unprimed and granulocyte colony-stimulating factor-mobilized peripheral-blood stem cells.

PURPOSE: To evaluate (1) the effect of granulocyte colony-stimulating factor (G-CSF) on peripheral-blood stem-cell (PBSC) mobilization; (2) the rate of hematopoietic recovery after G-CSF-mobilized PBSC transplantation; and (3) the outcome of high-dose myeloablative therapy and PBSC transplantation in patients with relapsed or refractory lymphoma. PATIENTS AND METHODS: Ninety-five patients with lymphoma underwent high-dose therapy followed by PBSC transplant in three sequentially treated cohorts of patients in a nonrandomized study. The first 30 patients received nonmobilized PBSCs (unprimed) without G-CSF after transplant, the next 26 patients received PBSC that were mobilized with G-CSF 5 micrograms/kg/d (primed-5) plus G-CSF after transplant, and the last 39 patients received PBSC mobilized by G-CSF 10 micrograms/kg/d (primed-10) plus G-CSF after transplant. The conditioning regimen consisted of fractionated total-body irradiation (FTBI) 12 Gy in combination with etoposide 60 mg/kg and cyclophosphamide 100 mg/kg. Patients with prior radiotherapy received carmustine (BCNU) 450 mg/m2 instead of FTBI. RESULTS: The use of G-CSF-mobilized PBSCs in combination with G-CSF posttransplant resulted in a significantly accelerated time to recovery of both granulocyte and platelet when compared with the unprimed group. The median number of days to an absolute granulocyte count (ANC) of greater than 0.5 x 10(9)/L was 10 days for G-CSF primed versus 20 days for the unprimed (P = .0001). The median days to platelet transfusion independence was 16 and 31 days (P = .0001) for the G-CSF primed and unprimed, respectively. There were also significant reductions in the number of platelet (P = .02) and RBC transfusions (P = .006) for the G-CSF primed. Multivariate analysis of prognostic factors identified CD34+ cell dose as the only additional factor predicting engraftment. Sixty-nine patients are alive at a median follow-up of 15.9 months (range, 7.4 to 63.7). The cumulative probability of 2-year disease-free survival is 59% (95% confidence interval [CI], 36% to 79%) and 39% (95% CI 25% to 55%) for patients with Hodgkin's disease and non-Hodgkin's lymphoma, respectively. CONCLUSION: The use of G-CSF-mobilized PBSC after high-dose myeloablative therapy resulted in a rapid, complete, and sustained hematopoietic recovery. Disease-free survival over 2 years can be achieved in some patients with relapsed lymphoma after high-dose therapy and PBSC transplantation. However, longer follow-up is required to confirm the curability of this approach.

Adolescent↗
PubMed1994

Detection of the Philadelphia chromosome in paraffin-embedded tissue by fluorescence in situ hybridization.

The bcr-abl fusion gene situated on the Philadelphia chromosome is a tumor-specific marker for chronic myelogenous leukemia. We evaluated the usefulness of two color fluorescence in situ hybridization with bcr and abl probes as a means of detecting the Philadelphia chromosome in formalin-fixed, paraffin-embedded sections of spleen and lymph node specimens from eight patients with myeloproliferative diseases showing clinical and morphological features of chronic myelogenous leukemia in accelerated phase. Our analysis showed co-localized hybridization signals corresponding to the bcr-abl fusion product in tissue sections from six patients previously found to have the Philadelphia chromosome by conventional cytogenetics and polymerase chain reaction. The two remaining specimens lacked bcr-abl fusion signals and were obtained from patients who were negative for the Philadelphia chromosome by cytogenetic and polymerase chain reaction analysis. We conclude that fluorescence in situ hybridization is a sensitive method for the detection of the bcr-abl fusion gene in histological specimens from patients with chronic myelogenous leukemia. The technique may become a useful tool in the evaluation of tissue specimens from patients with chronic myelogenous leukemia and related Philadelphia chromosome-positive hematologic malignancies.

Fusion Proteins, bcr-abl↗
PubMed1993

Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission.

Ninety-nine consecutive patients with acute leukemia in first complete remission under age 50 (median age 27 years; age range 1 to 47 years) with a histocompatible sibling donor were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation. Sixty-one patients were diagnosed with acute myelogenous leukemia (AML), 34 patients with acute lymphoblastic leukemia (ALL), 3 patients with biphenotypic acute leukemia, and 1 patient with acute undifferentiated leukemia. Thirty of the 34 patients with ALL had at least one of the following high-risk factors: age greater than 30, white blood cell count at presentation > 25,000/microL, extramedullary disease, certain chromosomal translocations, or the need for greater than 4 weeks of induction chemotherapy to achieve first complete remission. Cumulative probabilities of disease-free survival and relapse at 3 years were 61% and 12%, respectively, for the 61 patients with AML and 64% and 12%, respectively, for the 34 patients with ALL. By stepwise Cox regression analysis, significant prognostic variables for patients with acute myelogenous leukemia were the presence of acute graft-versus-host disease and increasing age, whereas for patients with acute lymphoblastic leukemia, significant variables were age and the development of cytomegalovirus-associated interstitial pneumonia. Complications related to graft-versus-host disease and relapse of leukemia were the major causes of death.

Adolescent↗
PubMed1993

Ribozyme-mediated inhibition of bcr-abl gene expression in a Philadelphia chromosome-positive cell line.

The bcr-abl fusion gene is the molecular counterpart of the Philadelphia chromosome (Ph1) and is directly involved in the pathogenesis of Ph1+ leukemia. Inhibition of bcr-abl gene expression may have profound effects on the cell biology of Ph1+ cells, as recent experiments with antisense oligonucleotides have shown. In this study we have designed and synthesized a unique ribozyme that is directed against bcr-abl mRNA. The ribozyme cleaved bcr-abl mRNA in a cell-free in vitro system. A DNA-RNA hybrid ribozyme was then incorporated into a liposome vector and transfected into EM-2 cells, a cell line derived from a patient with blast crisis of chronic myelogenous leukemia. The ribozyme decreased levels of detectable bcr-abl mRNA in these cells, inhibited expression of the bcr-abl gene product, p210bcr-abl, and inhibited cell growth. This anti-bcr-abl ribozyme may be a useful tool to study the cell biology of Ph1+ leukemia and may ultimately have therapeutic potential in treating patients with Ph1 leukemias.

Base Sequence↗
PubMed1993

Effects of pentobarbital on inotropic state of isolated canine left ventricle.

Although pentobarbital has been found to depress myocardial function, the magnitude of its direct effects on ventricular contraction at anesthetic concentrations has not been well quantified. The direct effects of pentobarbital on left ventricular function were measured by employing an isolated canine heart preparation with a blood oxygenator. Seven hearts were perfused with blood, dextran, and perfluorochemical artificial blood. Ventricular function was evaluated using the slope of the end-systolic pressure-volume relationship (Ees) and the maximal rate of pressure development (dP/dtmax) in ventricles contracting isovolumically in control, after a low dose (13 micrograms/ml), and after a high dose (48 micrograms/ml) of pentobarbital. These concentrations represent one-half and two times the typical value (25 micrograms/ml) found to produce anesthesia in canines (assessed by tail clamp or blink reflex). The low dose of pentobarbital did not produce clear-cut depression in contractile function. The high dose of pentobarbital produced significant reductions of Ees, and dP/dtmax: Ees decreased 29%, from a control of 4.30 +/- 0.84 to 3.05 +/- 0.49 mmHg/ml and dP/dtmax decreased 24%, from a control of 909 +/- 148 to 695 +/- 173 mmHg/s. Thus, the threshold for the direct depressant effect of pentobarbital on ventricular function falls within the range of half to double the typically-reported anesthetic concentrations.

Animals↗
PubMed1992

High-dose chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy during first complete remission in adult patients with poor-risk aggressive lymphoma: a pilot study.

Twenty consecutive patients with poor-risk aggressive lymphoma who at presentation either had elevated serum lactic dehydrogenase level (LDH) and any one of the other poor-prognostic features: bulky mass greater than or equal to 10 cm, advanced stage III or IV, and greater than or equal to 2 extranodal sites, or normal LDH level and all other three features, underwent high-dose chemo/radiotherapy followed by unmanipulated autologous bone marrow transplantation (BMT) during their first complete remission. Eighteen had B-cell lymphoma and 2 had T-cell lymphoma. Eleven patients had high-grade (7 immunoblastic, 3 small noncleaved, non-Burkitt's, and 1 Burkitt's) and 9 had diffuse large cell lymphoma. All patients had achieved a complete remission following conventional chemotherapy. Four patients had also received involved field radiotherapy to areas of bulky disease. The preparative regimen consisted of high-dose etoposide 60 mg/kg and cyclophosphamide 100 mg/kg in combination with fractionated total body irradiation (FTBI) 1,200 cGy (15 patients), or single-dose TBI 750 cGy (2 patients), or carmustine 450 mg/m2 (3 patients). All patients tolerated the treatment well and achieved complete hematologic recovery. Three patients have relapsed at days 79, 196, and 401 after transplantation. Seventeen patients (84%) are alive and relapse-free with a median follow-up of 34 months (range 2 to 54). We conclude that high-dose chemo/radiotherapy followed by autologous BMT can be given as consolidation therapy during first remission in these patients with minimal transplant-related toxicity.

Adult↗
PubMed1991

Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission.

Fifty-three patients with high-risk acute lymphoblastic leukemia (ALL) under age 50 with a histocompatible sibling donor received high-dose radiochemotherapy followed by allogeneic bone marrow transplantation (BMT). The high-risk factors used to identify the patients were: white blood cell count at initial presentation, cytogenetic abnormalities, age, extramedullary leukemic infiltration, and time from initial therapy to complete remission. Patients with one or more of the above risk factors who received BMT have a disease-free survival of 61% with a median follow-up of 66 months (range 11 months to 10.6 years), and an actuarial relapse rate of 10%. This study demonstrates that patients with high-risk ALL achieve a significant disease-free survival and cure rate with the use of allogeneic fully matched sibling BMT. However, a properly designed prospective study comparing the outcome of BMT with the best currently available chemotherapy data is required to define the ultimate role of BMT in this group of patients.

Adolescent↗
PubMed1991

Persistence of bcr-able gene expression following bone marrow transplantation for chronic myelogenous leukemia in chronic phase.

The bcr-abl RNA transcript is the molecular counterpart of the Philadelphia chromosome and is detectable by an extremely sensitive polymerase chain reaction assay in most patients with chronic myelogenous leukemia. To determine the effectiveness of ablative radiochemotherapy and bone marrow transplantation in eradicating molecular evidence of the malignant clone, we assayed for bcr-abl RNA expression in specimens from 19 patients with CML in chronic phase (CP) who have survived for at least one year post-BMT. We correlated these results with the patients' remission status based on cytogenetic analysis and BM morphology, and with evidence of mixed hematopoietic chimerism by analysis of RBC antigen and DNA restriction fragment length polymorphism patterns. Thirteen of the 19 patients had detectable bcr-abl RNA at some time following BMT. Twelve of these patients have remained in remission by morphologic and karyotypic criteria from 16.6 to 63.7 months following BMT. One of these 13 patients relapsed both by cytogenetic and clinical criteria at 28.1 months after BMT. Six of these 13 patients are still positive at the time of their most recent analysis. Only two patients have evidence for mixed chimerism of normal hematopoietic elements by either RBC antigen or DNA RFLP patterns. These results suggest that, in some patients transplanted for CML in CP, small numbers of residual leukemic cells may persist or reappear transiently without leading to clinical relapse. The definition of complete remission in CML may need to be revised in light of the enhanced ability to detect minimal residual disease by PCR technology.

Adult↗
PubMed1991

Clinical evaluation of a dentinal adhesive system: three-year results.

The dentinal adhesive Scotchbond 2 was evaluated with the microfilled composite resin Silux in cervical and root caries lesions for up to 3 years. Clinical criteria evaluated included retention, marginal integrity, marginal discoloration, color match, anatomic form, recurrent caries, gingival response, and postoperative sensitivity. Overall, the adhesive demonstrated improved performance over earlier dentinal adhesive systems. Retention was greatest at 3 years when available enamel margins had been etched (93%) and when root caries lesions (97%) had been restored. Other criteria were reported as generally favorable. Early findings suggest that the level of development of sclerotic dentin may influence behavior of the adhesive. The greatest difficulty was noted in lesions presenting with heavy sclerotic dentin.

Acid Etching, Dental↗
PubMed1991

Exacerbation of inflammatory demyelinating polyneuropathy after bone marrow transplantation.

Two patients with hematologic malignancy and quiescent inflammatory demyelinating polyneuropathy developed severe exacerbations of polyneuropathy at the time of bone marrow transplantation. The clinical course in both patients was progressive despite therapy with immuno-suppressive agents, plasmapheresis, and high dose immunoglobulin. The polyneuropathy resulted in quadriplegia which contributed to the patients' deaths 175 and 48 days after transplantation. Sections of multiple peripheral nerves sampled post mortem in the first case revealed prominent demyelination with heavy infiltration of macrophages and lymphocytes. Immunohistochemical studies demonstrated that most of the lymphocytes were of the CD8+, cytotoxic/suppressor cell class and that many of the Schwann cells expressed class II (HLA-DR) antigen. This report suggests that bone marrow transplantation can exacerbate inflammatory demyelinating polyneuropathy.

Adult↗
PubMed1990

Human serum and plasma have different sources of epidermal growth factor.

Epidermal growth factor (EGF) was determined by radioimmunoassay in serum, plasma, and urine of 23 patients undergoing ablative therapy followed by bone marrow transplantation. The difference between the serum and plasma values reflected the amount of EGF released from the platelets at the time of blood coagulation. Platelet-derived EGF strongly correlated with platelet count (r + 0.850, P less than 0.0001), and the intercept of the regression line was very close to zero; one platelet contained approximately 2.5 x 10(-18) g EGF. Correspondingly, when the platelet count dropped after bone marrow ablation from 222 +/- 97 to 33 +/- 13 x 10(9)/l, the serum EGF decreased from 603 +/- 222 to 65 +/- 41 pg/ml (P less than 0.0001). Plasma EGF content did not correlate with the platelet count and did not change significantly after bone marrow ablation (before and after the ablation, correspondingly, 290 +/- 80 and 332 +/- 99 pg/ml, P = 0.194). High-performance liquid chromatographic fractionation of serum and plasma showed different molecular mass distribution of EGF-immunoreactive fractions. The main molecular mass components of the plasma EGF did not change after bone marrow ablation. Urine excretion remained unchanged (320 +/- 133 and 314 +/- 173 pmol EGF/mmol creatinine). We conclude that whereas platelets are the source of serum EGF, the origin of plasma EGF is different and the search of its origin is warranted.

Adult↗
PubMed1990

Expression of GlN1-immunoreactive glycoproteins during development and regeneration in avian peripheral nerve.

Reactivity of the monoclonal antibody GlN1 was examined by immunocytochemistry and immunoblotting in quail and chick developing and regenerating wing nerves; its distribution is compared to that of HNK-1 which detects a carbohydrate epitope widely distributed in the nervous system. Reactivity was detected by immunofluorescence in cryostat sections, by a postembedding electron-microscopic immunogold technique and in immunoblots of nerve homogenates. From E11-E16, reactivity was detected in several large (120-260 kD) glycoprotein bands; and thereafter, principally, in 3 myelin-related glycoproteins (100, 26.5, and 21.5/ 19.5 kD). The HNK-1 carbohydrate epitope was detected in all these and in other bands permitting identification of the 100-kD moiety as the myelin-associated glycoprotein and the 26.5-kD protein as the P0 protein; the myelin-related 21.5/19.5-kD doublet appears as distinct, probable adhesion molecule(s). During development and regeneration, GlN1 reactivity detected by immunogold labeling of sections appeared first over the extracellular matrix, and later over thicker myelin sheaths. After transection, immunoreactivity in immunoblots was lost in distal stumps but reappeared with time; first in the larger (greater than 120 kD) moieties and then in the myelin-related bands, the same sequence observed in development. Electron-microscopic detection of both GlN1 and HNK-1 carbohydrate epitopes by immunogold labeling of resin-embedded sections is localized most consistently in the thicker (greater than 0.3 microns) myelin sheaths of nerves from chicks at or after hatching. Immunoblots of mature fowl nerve tissues homogenized at various stages of preparation for electron microscopy (after fixation or after fixation and dehydration) show sustained immunoreactivity in the 21.5/19.5-kD bands, reduction or complete suppression in others, and evidence of immunoreactivity in high molecular weight, presumably cross-linked, constituents that remain in the stacking gel portion of the blots.

Animals↗
PubMed1990

Treatment of chronic myelogenous leukemia with bone marrow transplantation.

BMT is the only curative therapy for CML, a uniformly lethal malignant disorder of the hematopoietic stem cell. Younger patient age and transplant in CP are associated with better outcome. Transplant within 1 year of diagnosis may provide a greater chance of survival than transplant at a longer interval from diagnosis. T-cell depletion of donor BM significantly reduces the incidence of acute and chronic GVHD, but is associated with an increased risk of graft failure and a marked increase in rate of relapse. Early results suggest that HLA-matched or partially HLA-mismatched unrelated donors may be used successfully in cases in which a suitably matched related donor is not available. Autologous transplantation of BM or PB stem cells can result in successful engraftment and possibly prolonged survival in some patients with CML. Following allogeneic BMT, some patients relapse cytogenetically without progressing to hematologic relapse. The use of PCR methodology to amplify bcr-abl transcripts has revealed persistence of the malignant clone in a substantial number of patients who are in hematologic and cytogenetic remission. The clinical significance and biologic mechanism(s) of this form of molecular relapse remain to be defined.

Bone Marrow Transplantation↗
PubMed1989

Detection by enzymatic amplification of bcr-abl mRNA in peripheral blood and bone marrow cells of patients with chronic myelogenous leukemia.

The Philadelphia chromosome of chronic myelogenous leukemia (CML) patients is caused by a translocation of the c-abl gene from chromosome 9 to the breakpoint cluster region (bcr) on chromosome 22. A new bcr-abl mRNA is expressed in these cases. We have developed a modified polymerase chain reaction (PCR) for the detection of this mRNA. The method is extremely sensitive, reliable, and relatively fast. The analysis of peripheral blood or bone marrow cells from CML patients treated with chemotherapy shows that the two possible mRNAs are expressed in various combinations. Our results show that even after myeloablative therapy for bone marrow transplantation bcr-abl mRNAs are still expressed. Further studies, however, are necessary to determine the clinical relevance of a small number of persisting cells expressing the bcr-abl mRNA.

Blood Cells↗