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D Siegel

Publications and source records attributed to D Siegel.

At least 55 records · Page 3Linked to original sources
PubMed1998

Identification of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping.

Multicolor spectral karyotyping (SKY) was performed on bone marrow samples from 50 patients with multiple myeloma (MM) in anticipation of discovering new previously unidentified translocations. All samples showed complex karyotypes with chromosome aberrations which, in most cases, were not fully characterized by G-banding. Patients of special interest were those who showed add(14)(q32), add(8)(q24) and those whose G-banding karyotypes showed poor chromosome morphology. Three new recurring chromosome translocations not previously reported in MM were identified. Two of the translocations involve recurring aberrations at band 14q32.3, the site of the IgH locus, with different exchange partners. The most frequently recurring rearrangement was a subtle translocation at 14q32.3 designated as a t(14;16)(q32;q22 approximately 23), which was identified in six patients. A second and larger translocation at 14q32, identified in two patients, was designated as a t(9;14)(p13;q32), previously associated with Waldenstrom's macroglobulinemia and lymphoplasmacytoid lymphoma. A third translocation, identified in two patients, involved a whole-arm t(6;8)(p10;q10) translocation. The SKY technique was able to refine the designations of over 156 aberrations not fully characterized by G-banding in this study and resolved additional chromosome aberrations in every patient studied except two. The t(14;16)(q32;q22 approximately 23) identified by SKY in this study suggests this may be a frequent translocation in MM associated with complex karyotypes and disease progression. Therefore, the SKY technique provides a useful adjunct to routine G-banding and fluorescence in situ hybridization studies in the cytogenetic analysis of MM.

Chromosomes, Human, Pair 14↗
PubMed1998

Indolequinone antitumor agents: correlation between quinone structure, rate of metabolism by recombinant human NAD(P)H:quinone oxidoreductase, and in vitro cytotoxicity.

A series of indolequinones bearing various functional groups has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H:quinone oxidoreductase (NQO1) were studied. Thus 5-methoxyindolequinones were prepared by the Nenitzescu reaction, followed by functional group interconversions. The methoxy group was subsequently displaced by amine nucleophiles to give a series of amine-substituted quinones. Metabolism of the quinones by NQO1 revealed that, in general, compounds with electron-withdrawing groups at the indole 3-position were among the best substrates, whereas those with amine groups at the 5-position were poor substrates. Compounds with a leaving group at the 3-indolyl methyl position generally inactivated the enzyme. The toxicity toward non-small-cell lung cancer cells with either high NQO1 activity (H460) or no detectable activity (H596) was also studied in representative quinones. Compounds which were good substrates for NQO1 showed the highest selectivity between the two cell lines.

Antineoplastic Agents↗
PubMed1998

Collection, tumor contamination, and engraftment kinetics of highly purified hematopoietic progenitor cells to support high dose therapy in multiple myeloma.

Unfractionated peripheral blood stem cell (PBSC) grafts contain measurable quantities of myeloma cells and are therefore a potential source of relapse posttransplantation. In contrast, fluorescence-activated cell sorting (FACS)-sorted CD34+ Thy1+ Lin- peripheral blood cells are substantially enriched for stem cell activity, yet contain virtually no clonal myeloma cells. A study was performed in patients with symptomatic myeloma, who had received 12 months or less of preceding standard chemotherapy, to evaluate the feasibility of large scale purification of primitive hematopoietic stem cells in order to study engraftment kinetics posttransplantation and the degree of tumor cell contamination of this cell population, based on polymerase chain reaction (PCR) analysis for the patient-specific complementarity-determining region III (CDR III). PBSC were mobilized with high dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor (GM-CSF). A combination of elutriation and chemical lysis was used to deplete PBSC collections of monocytes, granulocytes, erythrocytes, and platelets. Subsequently, CD34+ Thy1+ Lin- progenitor cells were purified with high speed cell sorting. Of the 10 evaluable patients, nine met the required minimum criteria of >/=7.2 x 10(5) cells/kg to support tandem transplants. After high dose melphalan (200 mg/m2) eight engrafted successfully, although granulocyte (absolute neutrophil count [ANC] >0.5 x 10(9)/L, 16 days) and platelet recovery (platelets > 50 x 10(9)/L, 39 days) was substantially delayed when compared with unmanipulated PBSC grafts; one patient required infusion of a reserve graft because of lack of evidence of engraftment by day +28. Three patients proceeded to a second graft with high dose melphalan and total body irradiation; two required infusion of a reserve graft and both died of infectious complications; one showed delayed, but complete, engraftment after this myeloablative regimen. Two of the nine evaluable patients attained a clinical complete remission (CR). The grafts from three patients were tested for tumor contamination and contained no detectable clonal myeloma cells. Larger quantities of purified cells may be required to resolve the problem of delayed engraftment.

Adult↗
PubMed1998

Oligoclonal protein bands and Ig isotype switching in multiple myeloma treated with high-dose therapy and hematopoietic cell transplantation.

Multiple myeloma (MM) is usually characterized by production of a single serum monoclonal protein of constant isotype and light-chain restriction. Multiple Ig isotypes and isotype switches, which are rare in untreated patients, are reported to be more common in patients undergoing myeloablative therapy. These additional protein bands, detected by immunofixation electrophoresis (IFE), could be due to altered paraprotein production by the malignant plasma cell clone or oligoclonal Ig production during recovery of B-cell function after myeloablative therapy. We analyzed abnormal protein bands (APB), distinct from the presenting paraprotein, in 550 patients receiving high-dose therapy with autologous hematopoietic cell transplantation at a single institution. Fifty-five patients (10%) had APB, 48 had oligoclonal bands (OB), and 23 had an apparent isotype switch (IS) on IFE (16 had both OB and IS). Morphologic and flow cytometric examination of bone marrow in 17 patients with IS showed no evidence of a clonal plasma cell isotype switch. Patients with APB had significantly higher complete response to therapy (67% v 37%, P = .001). To assess the independent prognostic relevance of APB, a multivariate analysis was performed among 471 patients surviving at least 12 months from first transplant (all patients developing APB had done so by 12 months from first transplant). APB (in 50 patients) was a favorable feature for both event-free (rank 3, P = .004) and overall survival (rank 3, P = .0005). We propose that OB and IS are likely to be due to recovery of Ig production rather than alterations in the biology of the malignant plasma cell clone.

Antineoplastic Agents↗
PubMed1998

Indolequinone antitumor agents: relationship between quinone structure and rate of metabolism by recombinant human NQO1.

A series of indolequinones bearing various functional groups has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H:quinone oxidoreductase (NQO1), and on the toxicity toward nonsmall cell lung cancer cells with either high NQO1 activity (H460) or with no detectable activity (H596) were studied.

Antineoplastic Agents↗
PubMed1998

Lymphoceles after laparoscopic pelvic node dissection.

OBJECTIVE: Lymphocele formation has been infrequently reported as a complication of laparoscopic pelvic lymph node dissection (LPLND). We determined the incidence of clinical and subclinical lymphocele formation in patients undergoing transperitoneal LPLND. METHODS: Charts and radiological records of 111 patients undergoing transperitoneal LPLND at this institution between January 1991 and December 1995 were reviewed to determine the incidence of lymphocele formation. RESULTS: Of 111 patients undergoing LPLND, 12.6% had positive lymph nodes and received hormonal therapy. Radical retropubic (12) or perineal (28) prostatectomy was performed either simultaneously or within 2 weeks in 41% of the node-negative patients. Radiation therapy was the treatment modality in the remaining node negative patients (N = 57). Twenty-three patients undergoing radiation therapy had preplanning pelvic computed tomography (CT) scans 2 to 16 weeks (mean 8.2 weeks) after LPLND. These were reviewed by a single radiologist to determine the presence of subclinical lymphoceles. Seven patients (30.4%) had lymphoceles of varying sizes (3 large and 4 small). Although most were identified on CT scans 4 weeks after the procedure, two were identified on scans 12 and 16 weeks after the procedure (mean 6.5 weeks). None of these patients developed symptoms referable to or had treatment for the lymphocele during a 2 to 37 month follow-up (mean 20 months). Only two patients (3.5%) undergoing LPLND as an isolated procedure had clinical evidence of lymphocele formation, both of which were subsequently confirmed with CT scans (1 large, 1 small). One was treated with CT-guided drainage and sclerosis and the other resolved spontaneously. CONCLUSION: The clinical incidence of lymphocele formation following LPLND remains relatively low. Only a portion of these patients requires intervention. Subclinical lymphoceles, as detected on follow-up CT scans, occur with a much greater frequency. These seldom become symptomatic requiring treatment. Rather, they appear to resolve spontaneously. Nevertheless, clinical suspicion should remain high in order to detect and properly treat symptomatic lymphoceles when they occur.

Combined Modality Therapy↗
PubMed1998

Pharmacologic treatment of hypertension in the Department of Veterans Affairs during 1995 and 1996.

Patterns of antihypertensive drug use, the cost of this care and potential savings with changes of treatment patterns, were studied for all hypertensives treated at US Veterans Affairs (VA) medical facilities for fiscal years 1995 and 1996. Data was aggregated by individual medication as well as by antihypertensive drug class. Cost estimates were based on median cost and number of units for each dosage form of each medication dispensed at all facilities. Potential savings were estimated by substituting beta-blockers or diuretics for calcium antagonists. In a subset of patients the prevalence of hypertension, and among hypertensives the prevalence of coronary artery disease, congestive heart failure, and diabetes mellitus, was determined. For these patients, patterns of treatment by antihypertensive drug class was examined. For all VA facilities, of the 10 most frequently prescribed antihypertensives in 1995, four were calcium antagonists, two angiotensin converting enzyme (ACE) inhibitors, two beta-blockers, and two diuretics. In 1996, this was changed by the addition of an ACE inhibitor and the subtraction of a diuretic combination. Calcium antagonists accounted for 37% of treatment days in 1995 and 35% in 1996, ACE inhibitor use went from 34% to 36%, beta-blockers from 17% to 18%, and diuretic use remained at 12%. In 1996, approximately 86.6 million dollars were spent on calcium antagonists, 51.8 million on ACE inhibitors, 7.9 million on beta-blockers, and 3.6 million on diuretics. The estimated annual cost savings for each 1% conversion of calcium antagonists to beta-blockers would be $713,000 and to diuretics $758,000. In a subset of 7526 hypertensive patients with known comorbid conditions, calcium antagonists and ACE inhibitors were also the most commonly used drug classes for all categories of patients, including those without coronary artery disease, congestive heart failure, and diabetes mellitus. Calcium antagonists and ACE inhibitors were the most commonly dispensed antihypertensives at VA facilities for both 1995 and 1996, with a small decrease in calcium antagonist use from 1995 to 1996. The cost implications of these practice patterns as compared with the primary use of diuretics and beta-blockers are enormous.

Adrenergic beta-Antagonists↗
PubMed1998

Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft?

Forty-two patients allografted for multiple myeloma after not having attained at least a partial remission (n = 19) or after having experienced disease progression (n = 23) following one autograft were compared with 42 pair-matched controls who underwent salvage autotransplantation under identical conditions. Autografted controls were matched closely for albumin, C-reactive protein, creatinine, disease sensitivity, duration of standard therapy prior to the first transplant, Ig isotype, karyotype, LDH, and response to the first transplant, but, in comparison to allografted patients, were older, had higher beta2-microglobulin, and had a shorter interval between the two transplants. The complete remission rate was 41% after allogeneic and 33% after autologous transplantation (P = NS). The 3-year probability of event-free survival was comparable for the two groups (25 +/- 8% after autografting and 20 +/- 8% after allografting). The 3-year probability of survival was significantly higher after autologous transplantation (54 +/- 8% vs 29 +/- 9%; P = 0.01). Twenty-one patients in the autograft group were alive 11-59 months (median 32) following the second transplant, while 15 patients in the allograft group were alive at 10-53 months (median 20). The 3-year probability of disease progression was significantly lower after allogeneic transplantation (31 +/- 10% vs 72 +/- 9%, P = 0.03). The 1-year probability of transplant-related mortality was significantly higher after allografting (43 +/- 8% vs 10 +/- 5%; P = 0.0001). We conclude that while autografting appears to be superior to allografting for salvage therapy of myeloma persisting or relapsing after one previous autotransplant in terms of overall survival, event-free survival is comparable due to significantly lower disease progression after allografting. Reduction in allograft-related toxicity can potentially improve the results of allogeneic transplantation significantly.

Adult↗
PubMed1998

Fluoroscopically placed percutaneous gastrostomies in the head and neck patient.

OBJECTIVE: At our institution, percutaneous gastrostomy tubes have been inserted under fluoroscopic guidance (fluoroscopic cutaneous gastrostomy [FPG]), thereby avoiding the need to traverse the pharynx and esophagus with a large-bore esophagoscope. For this reason, placement in the postoperative patient does not jeopardize the surgical reconstruction. METHODS: Thirty-five patients underwent percutaneous gastrostomy placement under fluoroscopic guidance. These included 12 patients whose cervical esophagus could not be entered safely because of a lesion in the head neck, 11 patients who had recently undergone resection of a head and neck cancer with pharyngeal reconstruction where traditional percutaneous enteral gastrostomy (PEG) placement was contraindicated, and two patients with postoperative fistulae. RESULTS: Thirty-four of 35 patients underwent successful gastrostomy or gastrojejunostomy placement. One patient had an intrathoracic position of the stomach, and one patient required repeat placement because the tube dislodged 5 days after insertion. No tube occluded. CONCLUSIONS: Percutaneous gastrostomy under fluoroscopic guidance (FPG) is an effective, safe method for access for prolonged enteral feeding of the patient whose cervical esophagus cannot be accessed for a variety of reasons. It also allows the safe placement of a gastrostomy catheter when the patient's postoperative course becomes complicated and prolonged enteral nutrition is required.

Adult↗
PubMed1998

Comparable engraftment kinetics following peripheral-blood stem-cell infusion mobilized with granulocyte colony-stimulating factor with or without cyclophosphamide in multiple myeloma.

PURPOSE: To compare, in the setting of tandem autotransplantations for multiple myeloma (MM), two established methods of peripheral-blood stem-cell (PBSC) procurement with chemotherapy or hematopoietic growth factor alone. PATIENTS AND METHODS: Between June 1994 and July 1995, 44 patients with MM were randomized to PBSC mobilization with either granulocyte colony-stimulating factor (G-CSF) 16 microg/kg (group 1; n = 22) or high-dose cyclophosphamide (HDCTX) 6 g/m2 plus G-CSF 5 microg/kg (group 2; n = 22). All 44 patients received melphalan 200 mg/m2 with their first autograft and 32 patients proceeded to a second transplantation. RESULTS: Group 2 required a significantly longer time interval for completion of PBSC collection than group 1 (median, 22 v 8 days; P = .0001), greater frequency of hospitalization (100% v 32%; P = .0001), and increased transfusion of platelets (86% v 18%; P = .0001) and packed RBCs (86% v 55%; P = .02). Likewise, the incidence of fever and pneumonia/sepsis were higher in group 2 (P = .02 and P = .04, respectively). Surprisingly, despite greater CD34 cell quantities infused in group 2, median recovery times of granulocytes (both > 500/microL and 2,500/microL) and platelets (both > 50,000/microL and > 100,000/microL) were similar (all P > .7). Posttransplant toxicities were also similar. CONCLUSION: Compared with HDCTX plus G-CSF, high-dose G-CSF alone is associated with lower morbidity, shorter duration of PBSC mobilization, and comparable hematopoietic recovery after transplantation, which should result in significant cost reduction. Considering the relatively limited antitumor activity of HDCTX (10% with > or = 50% tumor cytoreduction), PBSC mobilization with HDCTX should be limited to selected patients with persistent MM despite induction chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Collection of more hematopoietic progenitor cells with large volume leukapheresis in patients with multiple myeloma.

Reinfusion of mobilized peripheral blood stem cells (PBSC) after high dose chemotherapy accelerates hematopoietic recovery. Because of the relatively low content of hematopoietic progenitors in the peripheral blood even after mobilization, multiple leukapheresis procedures are necessary to reach the required target number of CD34 cells to ensure prompt engraftment post-transplantation. Our previous studies have shown that the highest proportions of hematopoietic progenitors cells (CD34) are collected during the first three days of apheresis, whereas peak levels of myeloma cells are observed during subsequent days. Therefore, large volume leukapheresis (LVL), defined as processing of greater than 3 blood volumes or a total of at least 15 liters, was explored in 23 myeloma patients, undergoing 91 procedures; 14 patients were mobilized with high dose cyclophosphamide (6g/m2) and hematopoietic growth factors and 9 with G-CSF only. CD34 yields were measured separately for the first and last two hours of collection. We observed no decrease in CD34 cells/kg during the last two hours of collection and when the LVL collections were compared to historical matched controls, mobilized with the same regimen, the median quantity of CD34 cells/kg/liter collected remained equivalent during all days of apheresis. When compared to G-CSF only, mobilization with high dose cyclophosphamide appeared to result in superior hematopoietic stem cell collections. Interestingly, the G-CSF group experienced a progressive decrease in platelets during consecutive days of LVL, while the opposite was seen in the cyclophosphamide group. LVL procedures were not associated with a higher complication rate than standard volume apheresis. We conclude that LVL procedures allow collection of more CD34 cell per session while not jeopardizing progenitor cell collections during subsequent sessions. Since more CD34 cells are collected, fewer days are required to attain the optimal target of progenitor cells. This should result in PBSC grafts with less tumor contamination.

Antineoplastic Agents, Alkylating↗
PubMed1998

Epithelioid hemangioendothelioma of the liver mimicking Budd-Chiari syndrome.

A case of epithelioid hemangioendothelioma of the liver in a 34-year-old man with clinical and radiologic findings suggestive of Budd-Chiari syndrome is reported. Despite clinical and radiologic findings, percutaneous liver biopsy was suspicious for epithelioid hemangioendothelioma. The patient underwent liver transplantation 2 months later, and histologic examination confirmed this diagnosis. Unusual histopathologic features included extensive areas of capillary-thin vascular structures with open lumina, lack of significant cytologic atypia in the majority of neoplastic cells, and areas with Budd-Chiari-like features in the hepatic parenchyma surrounding the tumor. The neoplastic cells were focally immunopositive for endothelial markers, such as factor VIII-related antigen and CD34 antigen. The unusual clinical presentation may have been due to tumor invasion and fibrous obliteration of terminal hepatic venules and sublobular veins. Epithelioid hemangioendothelioma should be considered when evaluating patients with clinical features of Budd-Chiari syndrome or veno-occlusive disease.

Adult↗
PubMed1998

Immunohistochemical detection of NAD(P)H:quinone oxidoreductase in human lung and lung tumors.

NAD(P)H:quinone oxidoreductase (NQO1) is a flavoenzyme that catalyzes the two-electron reduction of quinones and related compounds. With the use of biochemical assays, NQO1 has been shown to be overexpressed in many types of cancer, including non-small cell lung cancer (NSCLC). NQO1 can bioactivate antitumor quinones such as mitomycin C, and new quinone-based drugs are currently being developed to target this enzyme in tumors such as NSCLC. Because there is no information on the cell-specific expression of NQO1 in lung, the purpose of this study was to examine the expression of NQO1 in human NSCLC, small cell lung cancer, carcinoid lung tumors, and normal lung using immunohistochemistry. A high level of NQO1 protein expression was detected by immunohistochemistry in NSCLC (adenocarcinoma, squamous cell carcinoma, and bronchoalveolar carcinoma), but no NQO1 protein could be detected in small cell lung cancer or carcinoid lung tumors. In addition, NQO1 protein expression was examined by immunohistochemistry in normal lung tissue. A high level of NQO1 protein expression was detected by immunohistochemistry in normal lung respiratory epithelium, with the highest levels of expression observed in ciliated columnar epithelial cells. Significant amounts of NQO1 protein were also detected in the vascular endothelium and adipocytes. These data demonstrate that NQO1 is overexpressed in NSCLC. Cells in normal lung also contain marked NQO1 protein and may be damaged by drugs activated by NQO1. These data validate NSCLC as a target for NQO1-directed agents and suggest that the potential for lung toxicity be considered in the preclinical development of quinone-based antitumor drugs.

Humans↗
PubMed1997

Purification of feline lysosomal alpha-mannosidase, determination of its cDNA sequence and identification of a mutation causing alpha-mannosidosis in Persian cats.

alpha-Mannosidosis is a lysosomal storage disorder that is caused by the deficiency of lysosomal alpha-mannosidase. Feline alpha-mannosidosis is a well-characterized animal model used for studying pathological and therapeutic aspects of lysosomal storage disorders. We here report the purification of feline liver lysosomal alpha-mannosidase and determination of its cDNA sequence. The active enzyme consisted of three polypeptides, with molecular masses of 72, 41 and 12 kDa, joined by non-covalent forces. The cDNA sequence of feline lysosomal alpha-mannosidase was determined from reverse transcriptase PCR products obtained from skin fibroblast mRNA. The deduced amino acid sequence contained the N-terminal sequences of the 72 and 41 kDa peptides. This indicated that the enzyme is synthesized as a single-chain precursor with a putative signal peptide of 50 amino acids followed by a polypeptide chain of 957 amino acids, which is cleaved into the three polypeptides of the mature enzyme. The deduced amino acid sequence was 81.1 and 83.2% identical with the human and bovine lysosomal alpha-mannosidases sequences respectively. A 4 bp deletion was identified in an alpha-mannosidosis-affected Persian cat by DNA sequencing of reverse transcriptase PCR products. The deletion resulted in a frame shift from codon 583 and premature termination at codon 645. No lysosomal alpha-mannosidase activity could be detected in the liver of this cat. A domestic long-haired cat expressing a milder alpha-mannosidosis phenotype than the Persian cat had a lysosomal alpha-mannosidase activity of 2% of normal. This domestic long-haired cat did not possess the 4 bp deletion, proving molecular heterogeneity for feline alpha-mannosidosis.

Amino Acid Sequence↗