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Biomedical subjects

S Lerner

Publications and source records attributed to S Lerner.

At least 37 records · Page 2Linked to original sources
PubMed1999

Electroporation-mediated topical delivery of vitamin C for cosmetic applications.

It is now medically recognized that sagging skin and other signs of degenerative skin conditions, such as wrinkles and age spots, are caused primarily by oxy-radical damage. Vitamin C (Vit. C), in the form of L-ascorbic acid (Asc), is the one vitamin that can accelerate wound healing, protect fatty tissues from oxidation damage, and play an integral role in collagen synthesis. It is known that the lipid-rich stratum corneum (SC) is a highly resistant barrier to chemical agents penetrating into the skin. This report describes the first feasibility study of electroporation-mediated topical delivery (EMTD) of Asc for potential cosmetic applications. Both a cream formulation (20% Asc) and a crystal suspension (33% Asc) were applied respectively to human cadaver skin and fresh surgical skin. Six exponential pulses at 60 or 100 V and pulse lengths of 2.7-30 ms were selected. EMTD was more effective on fresh human skin than on human cadaver skin. For both skin models, EMTD with cream resulted in a greater enhancement of Vit. C penetration than with suspension. The distribution of electrical fields through the SC, epidermis, and dermis is demonstrated in computer simulation. Assuming that this fresh skin model and certain experimental conditions simulate projected in vivo applications, EMTD of Vit. C may represent an alternative method to ameliorate skin aging.

Administration, Topical↗
PubMed1998

Deficiency of the ATM protein expression defines an aggressive subgroup of B-cell chronic lymphocytic leukemia.

The gene mutated in ataxia telangiectasia, ATM, on human chromosome 11q22-q23 is implicated in cell cycle control and DNA repair. Ataxia telangiectasia patients as well as ATM-deficient mice are immune deficient and develop lymphoproliferative disease. Abnormalities in 11q22.3-q23.1 have also been described in B-cell chronic lymphocytic leukemia (B-CLL). We analyzed B-CLL samples for loss of heterozygosity (LOH) using microsatellite markers located at the ATM (D11S2179), mixed-lineage leukemia (MLL; D11S1356), and BCL1 (D11S987) loci, all of which are located around 11q23. Five (14%) of 36 informative cases showed LOH at the ATM gene, and two of these five cases had LOH at the MLL gene. No LOH was detected at the BCL1 locus, and none of the cases showed LOH at the MLL gene without LOH at the ATM gene. Four of these five cases with LOH at the ATM gene were studied for ATM protein expression by Western blot analysis. All four cases lacked ATM protein. An additional 111 cases of B-CLL were studied for expression of ATM protein by Western blot analysis and RIA. Thirty-eight (34%) of these cases showed ATM levels <50% of that seen in normal lymphoid cells. No morphological or immunophenotypic difference was observed between ATM-deficient B-CLL cases and cases with normal ATM expression. However, patients with ATM deficiency had significantly shorter survival times (35.66 versus 97.3 months; P = 0.003) and more aggressive disease, suggesting that ATM is involved in the leukemogenesis of B-CLL. These data also suggest that the ATM gene may play a role in the reported 11q23 abnormality in B-CLL, which also characterizes an aggressive disease.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1998

Infections in patients with chronic lymphocytic leukemia treated with fludarabine.

BACKGROUND: Fludarabine, a purine analogue with activity in chronic lymphocytic leukemia, is usually well tolerated. Although serious infections after fludarabine therapy have been described, a systematic analysis of the risk factors for such infections in chronic lymphocytic leukemia is lacking. OBJECTIVE: To determine the risk factors for major infection in patients with chronic lymphocytic leukemia treated with fludarabine. DESIGN: Retrospective review of medical records. SETTING: Cancer center. PATIENTS: 402 patients with chronic lymphocytic leukemia not previously treated or treated with chlorambucil (with or without prednisone) who received fludarabine (30 mg/m2 of body surface area per day for 5 days) with or without prednisone at 4-week intervals. RESULTS: Infections occurred more often in previously treated (144 of 248 [58%]) than in previously untreated (53 of 154 [34%]) patients (P < 0.001). Listeriosis or pneumocystosis occurred in 12 of 170 (7%) previously treated patients receiving fludarabine plus prednisone, 0 of 78 previously treated patients receiving fludarabine alone, and 2 of 154 (1%) previously untreated patients receiving fludarabine plus prednisone (P = 0.003). Univariate analysis identified previous chemotherapy, advanced disease, failure to respond to fludarabine, elevated serum beta2-microglobulin level (P < 0.001), low serum albumin level (P = 0.024), elevated serum creatinine concentration (P = 0.008), and low granulocyte count (P = 0.003) as risk factors for infection. Multivariate analysis identified Rai stage III or IV (odds ratio, 1.98 [95% CI, 1.17 to 3.94]), previous treatment (odds ratio, 2.24 [CI, 1.43 to 3.51]), and elevated serum creatinine concentration (odds ratio, 1.98 [CI, 1.09 to 3.67]) as statistically significant independent risk factors for major infection. A baseline granulocyte count of more than 1000 cells/microL was protective (odds ratio, 0.54 [CI, 0.29 to 0.99]). Five (26%) of 19 patients with a CD4 count less than 50 cells/mL developed cutaneous zoster compared with 9 (6%) of 139 patients with a CD4 count greater than 50 cells/mL (P = 0.01). CONCLUSIONS: Fludarabine used in previously treated patients with chronic lymphocytic leukemia may be associated with infections involving T-cell dysfunction, such as listeriosis, pneumocystosis, mycobacterial infections, and opportunistic fungal and viral infections. Prophylaxis or presumptive therapy should be initiated in the appropriate setting.

Analysis of Variance↗
PubMed1998

Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy.

One hundred seventy-four patients with progressive or advanced chronic lymphocytic leukemia (CLL) have received initial therapy with fludarabine as a single agent or fludarabine combined with prednisone. The overall response rate was 78% and the median survival was 63 months. No difference in response rate or survival was noted in the 71 patients receiving fludarabine as a single agent compared with the 103 patients who received prednisone in addition. The median time to progression of responders was 31 months and the overall median survival was 74 months. Patients over the age of 70 years had shorter survivals. Patients with advanced stage disease (Rai III and IV) had a somewhat shorter survival than earlier stage patients. More than half the patients who relapsed after fludarabine therapy responded to salvage treatment, usually with fludarabine-based regimens. Second remissions were more common in patients who had achieved a complete remission on their initial treatment. The CD4 and CD8 T-lymphocyte subpopulations decreased to levels in the range of 150 to 200/microL after the first 3 courses of treatment. Although recovery towards normal levels was slow, the incidence of infections was low in patients in remission (1 episode of infection for every 3.33 patient years at risk) and decreased with time off treatment. There was no association of infections or febrile episodes with the use of corticosteroids or the CD4 count at the end of treatment and a poor correlation with the increase in CD4 counts during remission. Infectious episodes were less common in patients who had a complete response compared with partial responders. Richter's transformation occurred in 9 patients and Hodgkin's disease occurred in 4 patients. Five other patients died from other second malignancies. Fludarabine appears to be an effective initial induction therapy with a reasonable safety profile for patients with CLL.

Adult↗
PubMed1998

Chronic lymphocytic leukemia in the young patient.

Chronic lymphocytic leukemia is customarily considered a disease of the elderly. However, 10% of patients reported in a variety of clinical trials are less than 50 years of age. Because of the new approaches to treatment with purine analogs, bone marrow transplantations, and monoclonal antibodies, the time is appropriate for reconsideration to the approach to treatment of younger patients. It is now established that the characteristics which predict for prognosis in young patients are similar to those of patients who are older. However, the survival of patients younger than 55 years of age is significantly greater than those older than 55 years of age. The sex distribution appears to be similar in younger patients as with older patients. The response to treatment with purine analogs has enabled the development of procedures for autologous stem cell transplantation. Allogeneic transplantation is being used increasingly with full dose ablative approaches or modified, less intensive regimens. The new approaches to therapy hold promise for improved survival in this subset of patients. Increasingly these patients are being diagnosed at an earlier stage in association with routine physical examinations or laboratory tests for other procedures.

Adult↗
PubMed1997

Modulation of stress protein (hsp27 and hsp70) expression in CD4+ lymphocytic cells following acute infection with human immunodeficiency virus type-1.

This study was designed to assess the impact of acute human immunodeficiency virus (HIV-1) infection on host intracellular expression of the heat shock family of stress proteins (hsps). Experimental conditions were established wherein CD4+ lymphocytic cell lines undergo a synchronous HIV-1 infection cycle. During the early phase of infection, HIV-1 mRNA expression was restricted to singly and multiply spliced subspecies, with no genomic viral RNA present until 30 hr following infection. In contrast, hsp27 and hsp70 mRNA transcription appeared as early as 3-8 hr following viral infection. No corresponding induction was observed in mock-infected cells. Notably, hsp27 and hsp70 mRNA transcripts were down-regulated by 24 hr, concomitant to the first appearance of full-length genomic HIV-1 mRNA. Hsp27 and hsp70 mRNA transcripts reemerged at end stages of the viral replicative cycle, coincident to virion release and CD4 cell death. Similarly, a transient induction of de novo hsp27 protein expression occurred between 12 and 24 hr. The generated hsp27 stress response was viral dose-related, suppressed by heat-inactivation of virus, and abrogated by neutralizing antibodies to HIV-1. Acute infection did not alter levels of hsp60, hsp70, and hsp90 protein synthesis. However, two-dimensional Western blot analysis did show the appearance of novel hsp70 homologues between 6 and 24 hr following infection. CEM.NKR, Jurkat, H9, and MT-2 cells showed similar patterns of viral-associated modulation of host hsp27 and hsp70 protein and RNA expression. Thus, host hsp27 and hsp70 stress pathways are selectively implicated in the HIV-1 viral life cycle.

Blotting, Northern↗
PubMed1997

Role of splenectomy in chronic lymphocytic leukemia.

BACKGROUND: The benefit of splenectomy, performed for complications of chronic lymphocytic leukemia (CLL) including autoimmune hemolytic anemia, thrombocytopenia, hypersplenism, and symptomatic splenomegaly, has not been clearly demonstrated. The objective of this study was to determine if splenectomy achieves a predictable hematologic and survival advantage over conventional chemotherapy in patients with CLL. STUDY DESIGN: A retrospective review was performed of 77 consecutive patients with CLL who underwent splenectomy between 1970 and 1994 at the University of Texas M. D. Anderson Cancer Center. Indications for splenectomy, pre- and postoperative hematologic profiles, response to splenectomy, and time to progression and death were recorded. Kaplan-Meier life tables were constructed, and a comparison to an age- and gender-matched cohort of CLL patients treated with fludarabine and no splenectomy was performed using log rank statistical analysis. RESULTS: Seventy-six percent of the patients studied were Rai stage III/IV. Twenty of 29 patients with hemoglobin counts (Hb) < or = 10 g/dL and 11 of 18 patients with platelet counts (plt) < 50 x 10(9)/L achieved an excellent hematologic response to splenectomy. Splenectomy significantly improved survival in patients with Hb < or = 10 g/dL or plt < or = 50 x 10(9)/L (p = 0.025). Thrombocytopenia did not significantly increase postoperative morbidity, and mortality rate was not significantly different between treatment groups. CONCLUSIONS: Splenectomy significantly improves survival in selected subgroups of patients with advanced-stage CLL over that achieved with conventional chemotherapy. Based on these results, splenectomy should be performed early in the course of the disease in CLL patients with either an Hb < or = 10 g/dL or plt < or = 50 x 10(9)/L.

Antineoplastic Agents↗
PubMed1997

Fludarabine and granulocyte colony-stimulating factor (G-CSF) in patients with chronic lymphocytic leukemia.

The study was designed to determine whether administration of granulocyte colony-stimulating factor (G-CSF) following fludarabine would reduce the incidences of myelosuppression and infections. Twenty-five previously treated patients with Rai stage III-IV chronic lymphocytic leukemia (CLL) received fludarabine 30 mg/m2 daily for 5 days each month. G-CSF was given at 5 microg/kg subcutaneously starting 1 day after chemotherapy (day 6) and continued until the next course unless the granulocyte count was > or =10000/microl. The incidences of myelosuppression and infection were compared with those seen in an historical control population of 145 previously treated patients with Rai stage III-IV CLL who were given the same schedule of fludarabine without growth factor. There was a significant decrease in myelosuppression; patients receiving G-CSF developed neutropenia at a neutrophil count <1000/microl or 500/microl in 45% and 15% of courses vs 79% (P=0.002) and 63% (P < 0.001) of historical controls. Twenty percent of G-CSF-treated patients had therapy delayed by >35 days per course, vs 50% of historical controls (P=0.005). The incidence of pneumonia was 8% with G-CSF and 37% without in historical controls. Other infection rates (sepsis, fever of undetermined origin, minor infections) were similar. This decrease in pneumonia was noted even in high-risk groups such as patients older than 60 years and patients with hypogammaglobulinemia. The use of G-CSF following fludarabine in high-risk patients with CLL resulted in a significant decrease in myelosuppression and pneumonia. Larger trials to verify these results and to compare costs are indicated.

Adult↗
PubMed1997

Allogeneic blood or marrow transplantation for chronic lymphocytic leukaemia: timing of transplantation and potential effect of fludarabine on acute graft-versus-host disease.

The outcome of allogeneic haemopoietic transplants including the rate of immune complications for patients with chronic lymphocytic leukaemia (CLL) refractory to or relapsing after chemotherapy with fludarabine was analysed. Fifteen patients with advanced CLL who received allogeneic transplantation were prospectively analysed. All patients had previously received chemotherapy with fludarabine for 3-15 courses; 12 were refractory. The median number of circulating CD4+ and CD8+ lymphocytes at the time of transplant was 0.49 x 10(9)/l and 0.23 x 10(9)/l, respectively. One patient was transplanted from a one HLA-antigen mismatched unrelated donor. Three others received a one or two antigen mismatched graft and 11 had HLA-identical sibling donors. Patients received cyclosporine or tacrolimus in addition to methotrexate or methylprednisolone for prophylaxis of acute graft-versus-host disease (aGVHD). Fourteen patients engrafted; one patient had graft failure, but recovered after therapy with intravenous immunoglobulin. 13 (87%) achieved complete remission (CR). Nine (53%) remain alive and in CR with a median follow-up of 36 (range 3-60) months. None developed visceral graft-versus-host disease. These data compared favourably to published reports in other leukaemia patients and for patients with CLL who received a comparable immunosuppressive therapy but without prior fludarabine exposure. This data indicates that allogeneic haemopoietic transplantation can induce durable remission in patients with CLL refractory to fludarabine and that it is reasonable to delay transplantation until failure of fludarabine therapy. It also suggests that prior exposure to fludarabine may decrease the incidence of severe aGVHD, possibly through its immunosuppressive effects. Further studies are warranted to evaluate this observation.

Adult↗
PubMed1996

Clinical experience with fludarabine in hemato-oncology.

Fludarabine monophosphate (Fludara) is a purine analogue which entered clinical trials in 1982. Although inactive in solid tumors, Fludara has marked activity in indolent lymphoproliferative disorders. The exact mechanism of action of Fludara is uncertain. Fludara has been established as the most active single agent in chronic lymphocytic leukemia (CLL) in single arm and comparative clinical trials. The activity has been demonstrated in both previously treated and initially treated patients. Marked activity has been noted in patients with low grade lymphoma, in particular, those with a follicular morphology and in Waldenstrom's macroglobulinemia. Combinations of fludarabine with alkylating agents, anthracyclines, and anthraquinones have led to clinically useful combination approaches. The ability of fludarabine to modulate the levels of the triphosphate form of cytosine arabinoside (ara-C) in acute leukemia cells has led to the development of combinations of fludarabine and ara-C. These combinations have demonstrated marked activity in treatment of relapsed and previously untreated patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The ability to modulate the activity of pyrimidines and to inhibit repair of DNA damage caused by alkylating agents, anthracyclines, and other DNA active drugs suggest that the future of fludarabine will be in combination approaches to modulate the activity of other agents. These activities may extend its role to use in solid tumors.

Antineoplastic Agents↗
PubMed1995

Interferon maintenance therapy for patients with chronic lymphocytic leukemia in remission after fludarabine therapy.

Many patients with chronic lymphocytic leukemia (CLL) achieve remission after treatment with fludarabine chemotherapy. Most of these patients, however, later experience relapse. In addition, immunologic deficits may persist even in patients in complete remission; lymphopenia, predominantly involving the CD4 population, is universal after fludarabine therapy. We used recombinant alpha interferon (IFN-alpha) maintenance therapy in patients with CLL who achieved remission in response to fludarabine therapy to determine its effect on residual disease, assessed by either bone marrow biopsy or flow cytometry, and on immune restoration. Thirty-one patients were treated with IFN-alpha (3 x 10(6) U by subcutaneous injection three times weekly). Twenty-two patients (71%) were in complete remission (CR) and nine (29%) were in partial remission (PR). Of the 22 patients in CR, 21 (95%) had evidence of residual disease at the start of IFN-alpha therapy. Low CD4 levels were noted in 93% of patients, low IgG levels in 45%, and anergy or hypoergy in 52%. Only one patient in PR achieved a CR on IFN-alpha therapy: the only patient who had had no prior fludarabine but had been treated with chlorambucil and prednisone. All patients in CR with minimal residual disease had persistent disease after IFN-alpha treatment. There were no increases in CD4 counts or IgG levels; three patients with borderline responses to skin testing had an increase in the number of positive tests while on IFN-alpha. The time to progression was no different in patients treated with IFN-alpha than in a historical control group of patients who had received no further therapy after fludarabine. In summary, the use of IFN-alpha maintenance did not eradicate residual disease, restore immune function, or prolong remissions in patients with CLL responsive to fludarabine.

Adult↗
PubMed1995

Survival of young patients with chronic lymphocytic leukemia failing fludarabine therapy: a basis for the use of myeloablative therapies.

We examined the survival of 91 young patients (< or = 55 years) with chronic lymphocytic leukemia from the time of failure of fludarabine therapy, in an attempt to identify those with a poor outcome who may benefit from investigative dose-intensive therapies. The median survival of patients unresponsive to fludarabine (n = 42) was 48 weeks, and only 11% responded to subsequent therapies. The median survival of patients relapsing following a fludarabine-induced remission (n = 49) was 87 weeks, and 83% of those who had received fludarabine as their first therapy (n = 14) responded to further fludarabine-containing therapies, with 60% alive at four years. Only 7% of those relapsing patients who had received fludarabine as salvage therapy (n = 35) responded to subsequent therapies (median survival 72 weeks). The poor outlook for these patients justifies the consideration of innovative dose-intensive therapies, such as bone marrow transplantation, with their attendant risk of toxicity.

Adult↗
PubMed1995

Fludarabine plus doxorubicin in previously treated chronic lymphocytic leukemia.

Based on the activity of fludarabine and doxorubicin in chronic lymphocytic leukemia (CLL), 30 patients received this combination. The median age of these patients was 61 years; median Zubrod performance status was one; median number of prior therapies was three; and median time to treatment was 53 months. Rai stage was 0 for two patients, I/II for 19 patients, and III/IV for nine patients. Prior treatment included fludarabine in 25 patients. In this regimen, fludarabine was administered as 30 mg/m2/d IV x 3 to 10 patients, 25 mg/m2/d IV x 4 to three patients, and to 17 patients as 30 mg/m2/d IV x 4. A 50 mg/m2 IV dose of doxorubicin was given to all patients. The first 17 patients received prednisone 30 mg/m2 x 5 days; however, this was discontinued due to other data demonstrating no therapeutic advantage and increased opportunistic infections when corticosteroids were added to fludarabine. Toxicity consisted primarily of infectious episodes: pneumonia nine, bacteremia one, FUO seven, and minor infection five. Two deaths from pneumonia occurred. Standard guidelines for response were used with the addition of a nodular CR group. Despite prior treatment with fludarabine in the majority of patients, the response rate in the 29 evaluable patients was CR 3%, nodular CR 17%, PR 35%, fail 38% and early death 7%. This combination of fludarabine and doxorubicin is active against CLL and warrants further study.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

A 3-day schedule of fludarabine in previously treated chronic lymphocytic leukemia.

This study was undertaken to determine the efficacy and toxicity of a shorter schedule of fludarabine administration (30 mg/m2 i.v. daily for 3 days every 4 weeks) in patients with previously treated chronic lymphocytic leukemia (CLL). Eighty patients with previously treated advanced (Rai III-IV) (54%) or progressive Rai stage 0-II (46%) were treated. The results of this trial were retrospectively compared with those of previous fludarabine trials using different schedules of administration. The complete response (CR), nodular CR and partial response rates were 10, 15 and 21%. The overall response rate (46%) was slightly lower than prior regimens using a 5-day schedule of fludarabine; however, this difference was not significant. Further evaluation by dual-parameter flow cytometry and immunoglobulin gene rearrangement analysis revealed that minimal residual disease was more common in a 3-day schedule. The overall incidence of infections per treatment course (14%) was significantly lower than that observed on the 5-day or weekly regimens (P < 0.001). The incidence of minor, atypical and viral infections were similar. There was no difference in survival in the various trials. In conclusion, a 3-day schedule of fludarabine in previously treated CLL patients was associated with a lower infection rate and similar survival to a 5-day schedule. These data support the use of a 3-day schedule of fludarabine as a single agent and in combination with other active agents.

Adult↗
PubMed1994

Deficient ileal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in sitosterolemia: sitosterol is not a feedback inhibitor of intestinal cholesterol biosynthesis.

We correlated the activity of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, with the sterol content and composition of mucosal cells from the ileum of three homozygous sitosterolemic subjects and one control subject. In this inherited disease, whole-body cholesterol biosynthesis is decreased and increased amounts of sitosterol are absorbed from the intestine and deposited in tissues. For comparison, similar measurements were obtained in the ileal mucosa of sitosterol-fed rats where sitosterol accounted for 11% of enterocyte sterols. In the three sitosterolemic homozygotes, sitosterol represented 9% to 11% of the total microsomal sterols in the intestinal mucosa, although normal architecture for both crypts and villi is observed. The mean ileal microsomal HMG-CoA reductase activity in the three homozygotes was less than half of control values. In the ileum of sitosterol-fed rats with increased mucosal sitosterol concentrations, microsomal HMG-CoA reductase activity was not inhibited. These results show that in three sitosterolemic homozygotes, abnormally low HMG-CoA reductase activity was detected in the ileum, as previously demonstrated in mononuclear leukocytes and liver. The failure of the increased tissue sitosterol pool to inhibit HMG-CoA reductase in rat ileum suggests that deficient cholesterol biosynthesis in homozygous sitosterolemia is inherited and is not due to feedback inhibition by tissue sitosterol.

Adult↗
PubMed1994

The effect of increased hepatic sitosterol on the regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol 7 alpha-hydroxylase in the rat and sitosterolemic homozygotes.

We investigated hepatic cholesterol homeostasis in four homozygous sitosterolemic subjects from two unrelated families who showed enhanced absorption, diminished removal and increased tissue and plasma concentrations of sitosterol (24-ethyl cholesterol). Measurements of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activities were correlated with steady state messenger RNA levels and related to cholesterol 7 alpha-hydroxylase activities in the sitosterolemic homozygotes and nine controls. Similar determinations were made in rats infused intravenously with sitosterol so that hepatic and plasma sitosterol concentrations increased to about 10% of total sterols to resemble the human disease sitosterolemia. In the four sitosterolemic homozygotes, hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activities were markedly reduced (12% of normal), and steady state 3-hydroxy-3-methylglutaryl coenzyme A reductase messenger RNA levels barely detected. In contrast, hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activities and messenger RNA levels were not decreased in rats with similarly elevated hepatic sitosterol concentrations. However, hepatic cholesterol 7 alpha-hydroxylase activity was inhibited 30% in both the sitosterolemic homozygotes and rats with high liver sitosterol concentrations. Plasma cholesterol concentrations increased 120% in the sitosterol-infused rats and 29% in the untreated human homozygotes. These results demonstrate that high-tissue sitosterol concentrations do not inhibit hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activityor steady state messenger RNA levels and that they competitively block cholesterol 7 alpha-hydroxylase activity and raise plasma cholesterol levels. Thus the deficiency of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the liver of sitosterolemic homozygotes is inherited and not due to the hepatic accumulation of sitosterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment.

Two hundred sixty-four patients with chronic lymphocytic leukemia were treated with fludarabine 30 mg/m2 intravenously for 30 minutes each day for 5 days and with prednisone 30 mg/m2 orally each day for 5 days. Courses were repeated monthly. Of the 264 patients. 125 patients (47%) had Rai stage III-IV disease; 169 patients (64%) were previously treated with a median of 3 prior regimens; and 138 of them (82%) were refractory to therapy with alkylating agents. The overall response (OR) and complete response (CR) rates in the 169 previously-treated patients were 52% and 37%; these were 74% and 63%, respectively, in Rai stage O-II patients and declined to 64% and 46%, respectively, in Rai III-IV disease. Among the previously untreated patients, the OR and CR rates were 79% and 63%, these being 85% and 70%, respectively, in Rai O-II patients, and declining to 64% and 46%, respectively, in Rai III-IV disease. The incidence of minor infections or fever of unknown origin was similar in all patient groups and occurred in 22% of courses. The incidence of sepsis and/or pneumonia was significantly correlated with the extent of prior therapy and with Rai stage, and ranged from 3% of courses in the previously untreated Rai O-II patients, to 13% of courses in the previously treated Rai III-IV patients. Listeria sepsis or Pneumocystis carinii pneumonia was noted in 14 patients. With therapy, CD4 levels were uniformly depressed from a median 1,015/microL pretreatment to a median 159/microL after 3 months of fludarabine therapy. Median time to progression in previously treated patients was 22 months. In previously untreated patients, median time to progression was 30 months for patients who achieved a partial remission and has not been reached in patients who achieved a CR with a median follow-up of 2 years. The median survival was 18 months for previously treated patients and has not been reached for previously untreated patients. Response rates in previously treated and untreated patients, as well as infection rates, were identical to those seen in 110 patients treated with the same dose schedule of fludarabine alone. Logistic regression analysis selected 4 factors to be significantly associated with worse response: Rai III-IV stage disease, prior therapy, older age, and low albumin levels. The regression equation was used to derive a probability of response based on the 4 characteristics. When the model was applied to the same population, patients could be divided into 4 prognostic groups with different outcomes.

Antigens, CD↗