Biomedical subjects

R Marcus

Publications and source records attributed to R Marcus.

At least 19 recordsLinked to original sources

PubMed2006

Severity of vertebral fracture reflects deterioration of bone microarchitecture.

INTRODUCTION: Bone microarchitecture, a component of bone strength, is generally measured on transiliac bone biopsy samples. The objective of this study was to determine whether assessment of four grades of vertebral fracture severity could serve as a noninvasive surrogate marker for trabecular bone volume and microarchitecture. METHODS: Baseline vertebral fracture severity was determined by semiquantitative assessment of spine radiographs from 190 postmenopausal women with osteoporosis. Bone-structure indices were obtained by 2D histomorphometry and 3D microcomputed tomography (CT) analyses. Significance of differences was determined after adjusting for age, height, and lumbar spine bone mineral density. RESULTS: There were significant (P < 0.05) trends in decreasing bone volume, trabecular number, and connectivity, and increasing trabecular separation with greater vertebral fracture severity. Histomorphometric bone volume was 25 and 36% lower (P < 0.05) in women with moderate and severe fractures than in women with no fractures, respectively. Compared with women without fractures, women with mild, moderate, and severe fractures had lower (P < 0.05) microCT bone volume (23, 30, and 51%, respectively). CONCLUSIONS: Microarchitectural deterioration was progressively worse in women with increasing severity of vertebral fractures. We conclude that assessment of vertebral fracture severity is an important clinical tool to evaluate the severity of postmenopausal osteoporosis.

Aged↗

PubMed2006

Response rate of bone mineral density to teriparatide in postmenopausal women with osteoporosis.

PURPOSE: It is desirable for clinicians to know what bone mineral density (BMD) response they can expect in women treated with osteoporosis therapies. The focus of this analysis was to determine what percentage of women attained a lumbar spine BMD response to teriparatide that equaled or exceeded the least significant change (LSC) value of 3%. METHODS: Data from three clinical trials involving postmenopausal women with osteoporosis were examined. The Fracture Prevention Trial was a double-blinded, placebo-controlled clinical trial examining the safety and efficacy of teriparatide 20 and 40 microg/day. The other two trials were double-blinded, head-to-head comparisons of alendronate 10 mg/day and teriparatide 20 or 40 microg/day, respectively. Only treatment-compliant women who had lumbar spine BMD measurements at all specified time points in these trials were included. For reference, we also examined the percentage of women with lumbar spine BMD responses to alendronate. Hip BMD responses that equaled or exceeded 3% were also examined. RESULTS: According to the LSC criteria, 91% of the teriparatide 20 microg/day group and 94% of the teriparatide 40 microg/day group were lumbar spine BMD responders at 18 months in the Fracture Prevention Trial. In the teriparatide 20 microg/alendronate head-to-head trial, 94% of women receiving teriparatide had a lumbar spine BMD response that equaled or exceeded the 3% criterion at 18 months compared to 75% of those receiving alendronate 10 mg/day (p < 0.01). In the teriparatide 40 microg/day group of the other head-to-head trial, 92% of women achieved the 3% criterion for the lumbar spine at 12 months compared to 69% of those receiving alendronate 10 mg/day (p < 0.01). The median 3-month change in amino-terminal extension peptide of procollagen type 1 [PINP] in women who had a lumbar spine BMD response to teriparatide at 18 months was larger than in women who did not have a lumbar spine BMD response. However, the median 3-month PINP change in lumbar spine BMD nonresponders still exceeded the LSC value of 10 microg/L. Although the percentage of teriparatide-treated women with a hip BMD response that met the 3% criterion was significantly greater than for placebo, there was no significant difference between the percentage of teriparatide 20 microg/day and alendronate 10 mg/day responders in the comparison trial. The baseline characteristics of teriparatide lumbar spine responders and nonresponders were similar. CONCLUSION: This analysis demonstrates that the vast majority of treatment-compliant postmenopausal women with osteoporosis and minimal prior bisphosphonate exposure have a lumbar spine BMD response to teriparatide that meets or exceeds the LSC. The characteristics of teriparatide responders and nonresponders were not significantly different; thus, we were unable to discern any characteristics that could be used to identify potential nonresponders.

Aged↗

PubMed2006

Re-assessment of risk factors for sporadic Salmonella serotype Enteritidis infections: a case-control study in five FoodNet Sites, 2002-2003.

Active surveillance for laboratory-confirmed Salmonella serotype Enteritidis (SE) infection revealed a decline in incidence in the 1990s, followed by an increase starting in 2000. We sought to determine if the fluctuation in SE incidence could be explained by changes in foodborne sources of infection. We conducted a population-based case-control study of sporadic SE infection in five of the Foodborne Diseases Active Surveillance Network (FoodNet) sites during a 12-month period in 2002-2003. A total of 218 cases and 742 controls were enrolled. Sixty-seven (31%) of the 218 case-patients and six (1%) of the 742 controls reported travel outside the United States during the 5 days before the case's illness onset (OR 53, 95% CI 23-125). Eighty-one percent of cases with SE phage type 4 travelled internationally. Among persons who did not travel internationally, eating chicken prepared outside the home and undercooked eggs inside the home were associated with SE infections. Contact with birds and reptiles was also associated with SE infections. This study supports the findings of previous case-control studies and identifies risk factors associated with specific phage types and molecular subtypes.

Adolescent↗

PubMed2006

Human factors in pediatric anesthesia incidents.

BACKGROUND: Anesthesia and the operating theater environment is a complex system involving man-machine and human-human interactions. Although we strive for an error free system, we are humans and errors and mistakes will occur. The aim of this study was to investigate the human factors behind events and incidents in pediatric anesthesia at our institution. METHODS: This study consisted of a retrospective review and analysis of all contemporaneously reported anesthetic incidents between April 1, 2002 and March 31, 2004 at Birmingham Children's Hospital. Where there were anesthetic human factors involved in the event these were classified. RESULTS: There were 668 incidents reported, giving a rate of 2.4% of the 28 023 anesthetics recorded. Airway and respiratory incidents were the most common representing 52.2% of all incidents. A total of 284 anesthetic human factors could be identified and classified. Of these the most common were errors in judgment 43%, failure to check 17.8%, technical failures of skill 9.2%, inexperience 7.7%, inattention/distraction 5.6% and communication issues 5.6%. CONCLUSIONS: In our institution anesthetic human factors occur in 42.5% of in-theater incidents in pediatric anesthesia. Knowledge of these is necessary so that changes can be made in practice both by individuals and departments of anesthesia, to make anesthesia as safe as possible.

Anesthesia↗

PubMed2005

Association of sex steroid hormones with brain morphology and cognition in healthy elderly men.

BACKGROUND: There is inconsistent evidence of the presence and direction of the relationship between sex hormone concentrations and cognitive function in older men, and there is little published literature on the relationship of sex hormone concentrations and brain volume as measured by MRI. OBJECTIVE: To examine the hypothesis that midlife total serum concentrations of testosterone (T), estradiol, estrone, and sex hormone binding globulin (SHBG) predict cognitive task performance and regional brain volumes at 10- to 16-year follow-up, in a longitudinal sample of World War II veteran twin men. METHODS: Treating twins as individuals, linear regression models were used, adjusting analyses for age, education, depressive symptomatology, blood pressure, alcohol consumption, years of cigarette smoking, and APOE epsilon4 allele status. RESULTS: There were no significant associations between sex hormone or SHBG concentrations and performance on a series of cognitive tasks measuring global and executive function, visual and verbal learning and memory. Higher midlife T concentrations were associated with larger hemispheric, frontal, and parietal regional brain volumes and with smaller left occipital brain volume. Higher estradiol and estrone concentrations were also associated with smaller right (estradiol) and both right and left (estrone) occipital volumes, but with no other brain regions. Owing to the multiple comparisons conducted, some significant associations may have occurred by chance. CONCLUSIONS: Overall, the pattern of results suggests a role for sex hormones in brain volume that predates potentially observable associations between sex hormones and cognitive task performance.

Aged↗

PubMed2004

Lenograstim after autologous peripheral blood progenitor cell transplantation: results of a double-blind, randomized trial.

A phase III, randomized, double-blind, placebo-controlled, multi-center trial was conducted in order to compare the incidence of microbiologically defined infections occurring after high-dose chemotherapy (HDT) and ASCT in 98 patients given lenograstim (Granocyte) and 94 patients given placebo after transplantation. Hematopoietic recovery, the use of i.v. antibiotics, the numbers of red blood cell and platelet transfusions, the days spent in hospital, and the days on parenteral nutrition were also compared. The incidence of infections until neutrophil recovery was significantly less in patients who received lenograstim after HDT and ASCT as compared to patients who received placebo (66 of 98 vs 86 of 94 patients, P<0.001). Lenograstim also significantly reduced the use of i.v. antibiotics (P<0.001) and the median duration of i.v. antibiotic treatment (8 days vs 10 days, P=0.04), improved neutrophil recovery (absolute neutrophil count >0.5 x 10(9)/l: 11 days vs 15 days, P<0.001) and reduced the number of days spent in hospital (15 days vs 17 days, P<0.001). The administration of lenograstim after HDT and ASCT significantly reduces the incidence of microbiologically defined infections until neutrophil recovery. It also leads to less use of antibiotics and earlier discharge from hospital.

Adjuvants, Immunologic↗

PubMed2004

The muscle strength and bone density relationship in young women: dependence on exercise status.

AIM: Numerous studies report an association between muscle strength and bone mineral density (BMD) in young and older women. However, the participants are generally non-athletes, thus it is unclear if the relationship varies by exercise status. Therefore, the purpose was to examine the relationships between BMD and muscle strength in young women with markedly different exercise levels. METHODS EXPERIMENTAL DESIGN: cross-sectional. SETTING: a University research laboratory. PARTICIPANTS: 18 collegiate gymnasts and 22 age- and weight-matched recreationally active control women. MEASURES: lumbar spine, femoral neck, arm, leg and whole body BMD (g/cm(2)) were assessed by dual X-ray absorptiometry. In addition, lumbar spine and femoral neck bone mineral apparent density (BMAD, g/cm(3)) was calculated. Handgrip strength and knee extensor and flexor torque (60 degrees /s) were determined by dynamometry, and bench press and leg press strength (1-RM) using isotonic equipment. RESULTS: BMD at all sites and bench press, leg press and knee flexor strength were greater in gymnasts than controls (p<0.001). In controls, knee extensor torque was significantly correlated to femoral neck, limb and whole body BMD (r=0.47-0.55, p<0.05), leg press strength was associated with limb and whole body BMD (r=0.52-0.74, p<0.05), and bench press strength with arm BMD (r=0.50, p=0.019). In partial correlations controlling for weight, leg press strength was related to leg and whole body BMD (r=0.46-0.63, p<0.05). There was no association between muscle strength and BMD in gymnasts. CONCLUSION: These results suggest that the association between muscle strength and BMD in young women is dependent on exercise status. The osteogenic effect of increased mechanical loading associated with gymnastics training likely contributes to the dissociation of the relationship in gymnasts.

Absorptiometry, Photon↗

PubMed2002

IGF-I regulates osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand in vitro and OPG in vivo.

IGF-I, a ubiquitous polypeptide, plays a key role in longitudinal bone growth and acquisition. The most predominant effect of skeletal IGF-I is acceleration of the differentiation program for osteoblasts. However, in vivo studies using recombinant human (rh) IGF-I and/or rhGH have demonstrated stimulation of both bone formation and resorption, thereby potentially limiting the usefulness of these peptides in the treatment of osteoporosis. In this study, we hypothesized that IGF-I modulates bone resorption by regulating expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL) in bone cells. Using Northern analysis in ST2 cells, we found that human IGF-I suppressed OPG mRNA in a time- and dose-dependent manner: 100 micro g/LIGF-I (13 nM) decreased OPG expression by 37.0 +/- 1.8% (P < 0.002). The half maximal inhibitory dose of IGF-I was reached at 50 micro g/liter ( approximately 6.5 nM) with no effect of IGF-I on OPG message stability. Conditioned media from ST2 cells confirmed that IGF-I decreased secreted OPG, reducing levels by 42%, from 12.1-7 ng/ml at 48 h (P < 0.05). Similarly, IGF-I at 100 micro g/liter (13 nM) increased RANKL mRNA expression to 353 +/- 74% above untreated cells as assessed by real-time PCR. In vivo, low doses of rhGH when administered to elderly postmenopausal women only modestly raised serum IGF-I (to concentrations of 18-26 nM) and did not affect circulating OPG concentrations; however, administration of rhIGF-I (30 micro g/kg.d) for 1 yr to older women resulted in a significant increase in serum IGF-I (to concentrations of 39-45 nM) and a 20% reduction in serum OPG (P < 0.05). In summary, we conclude that IGF-I in a dose- and time-dependent manner regulates OPG and RANKL in vitro and in vivo. These data suggest IGF-I may act as a coupling factor in bone remodeling by activating both bone formation and bone resorption; the latter effect appears to be mediated through the OPG/RANKL system in bone.

Animals↗

PubMed2002

Long-term predictions of the therapeutic equivalence of daily and less than daily alendronate dosing.

Less than daily alendronate dosing has been identified as an attractive alternative to daily dosing for patients and physicians. A recent 2-year study found bone mineral density (BMD) changes caused by weekly alendronate dosing therapeutically equivalent to that caused by daily dosing. There are no methods that can be used to predict how long therapeutic equivalence will be maintained after the first 2 years of treatment. In addition, it is unclear if dosing less frequently than weekly also might be therapeutically equivalent to daily dosing. In this study we use a computer simulation to develop predictions of the therapeutic equivalence of daily and less than daily dosing over time periods as long as a decade. The computer simulation uses a cell-based computer model of bone remodeling and a quantitative description of alendronate pharmacokinetics/pharmacodynamics (PK/PD). The analyses suggest that less than daily dosing regimens do not increase BMD as much as daily dosing. However, model predictions suggest that dosing as frequent as weekly still may be therapeutically equivalent to daily dosing over periods as long as 10 years. In addition, the simulations predict dosing less frequently than weekly may be therapeutically equivalent to daily dosing within the first year of treatment but may not be therapeutically equivalent after 10 years. Hypotheses based on these simulations may be useful for determining which dosing regimen may be most attractive for clinical trials.

Alendronate↗

PubMed2002

An expanded overview of postmenopausal osteoporosis.

Why is the incidence of osteoporotic fracture so much higher in women than in men? The dominant medical view holds that the exaggerated skeletal fragility and fracture risk of postmenopausal women solely reflects the loss of bone following withdrawal of endogenous estrogen. Indeed, an enormous amount of research in this area has attempted to understand the rise in fractures after menopause in terms of the impact of estrogen lack on bone remodeling. Recent insights suggest that this simple view does not offer an adequate explanation for the greater susceptibility of older women to fracture compared to that of men. It seems more reasonable to view bone health as a lifelong process, reflecting the contributions and influences of myriad events occurring throughout life to skeletal acquisition and maintenance. Only recently has the medical community recognized that the amount of bone present at skeletal maturity makes a powerful contribution to lifelong skeletal status. A second area that must be incorporated into discussions of this topic relates to bone size and geometry. Women's bones are inherently smaller than those of men. A bone's strength is determined by its size as well as by its material properties. In boys, pubertal increases in the cortical thickness of long bones are achieved by (testosterone-dependent) periosteal apposition. By contrast, increased cortical thickness in girls reflects bone expansion into the medullary space, with little or no periosteal apposition, suggesting an inhibitory effect of estrogen on the latter process. Consequently, at skeletal maturity, men have wider bones of greater mechanical competence. Although estrogen is generally held to be skeletally protective, this aspect of its actions may actually render women more susceptible to some fractures. In later life, men may lose even more bone from appendicular sites than do women, but men show much greater concomitant increases in periosteal apposition than women, permitting them to maintain a relatively favorable mechanical profile. These several findings are based on cross-sectional observations of relatively few individuals and therefore require confirmation in prospective longitudinal studies. The degree to which gender-related differences in later life skeletal adaptation reflects a bone's mechanical or metabolic environment has been frequently discussed but still awaits experimental confirmation.

Journal Article↗

PubMed2001

Activity of oral fludarabine phosphate in previously treated chronic lymphocytic leukemia.

PURPOSE: A prospective, multicenter, open-label phase II clinical trial was conducted to assess the efficacy and safety of oral fludarabine phosphate. Reference to an historical group of patients treated with the intravenous (IV) formulation allowed the investigators to compare the two formulations. PATIENTS AND METHODS: Efficacy was assessed using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) and National Cancer Institute (NCI) criteria for complete remission (CR), partial remission (PR), stable disease, or disease progression. Safety monitoring included World Health Organization (WHO) toxicity grading for all adverse events. RESULTS: Seventy-eight (96.3%) of 81 recruited patients with previously treated B-cell chronic lymphocytic leukemia (CLL) received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m(2)/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. According to IWCLL criteria, the overall remission rate was 46.2% (CR, 20.5%; PR, 25.6%). The comparative figures using NCI criteria were 51.3% (CR, 17.9%; PR, 33.3%). Overall, 30 incidents of severe adverse events were reported for 22 patients. WHO grade 3 or grade 4 hematologic toxicities included granulocytopenia (53.8%), leukocytopenia (28.2%), thrombocytopenia (25.6%), and anemia (24.4%). Gastrointestinal adverse events were more common with the oral formulation than previously reported with IV fludarabine phosphate. However, these events were generally mild to moderate. CONCLUSION: This study demonstrates that oral fludarabine phosphate has similar clinical efficacy to the IV formulation and a safety profile that is both predictable and essentially similar to that of the IV formulation.

Administration, Oral↗

PubMed2001

Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite.

BACKGROUND: It is unclear whether antimicrobial treatment after an Ixodes scapularis tick bite will prevent Lyme disease. METHODS: In an area of New York where Lyme disease is hyperendemic we conducted a randomized, double-blind, placebo-controlled trial of treatment with a single 200-mg dose of doxycycline in 482 subjects who had removed attached I. scapularis ticks from their bodies within the previous 72 hours. At base line, three weeks, and six weeks, subjects were interviewed and examined, and serum antibody tests were performed, along with blood cultures for Borrelia burgdorferi. Entomologists confirmed the species of the ticks and classified them according to sex, stage, and degree of engorgement. RESULTS: Erythema migrans developed at the site of the tick bite in a significantly smaller proportion of the subjects in the doxycycline group than of those in the placebo group (1 of 235 subjects [0.4 percent] vs. 8 of 247 subjects [3.2 percent], P<0.04). The efficacy of treatment was 87 percent (95 percent confidence interval, 25 to 98 percent). Objective extracutaneous signs of Lyme disease did not develop in any subject, and there were no asymptomatic seroconversions. Treatment with doxycycline was associated with more frequent adverse effects (in 30.1 percent of subjects, as compared with 11.1 percent of those assigned to placebo; P<0.001), primarily nausea (15.4 percent vs. 2.6 percent) and vomiting (5.8 percent vs. 1.3 percent). Erythema migrans developed more frequently after untreated bites from nymphal ticks than after bites from adult female ticks (8 of 142 bites [5.6 percent] vs. 0 of 97 bites [0 percent], P=0.02) and particularly after bites from nymphal ticks that were at least partially engorged with blood (8 of 81 bites [9.9 percent], as compared with 0 of 59 bites from unfed, or flat, nymphal ticks [0 percent]; P=0.02). CONCLUSIONS: A single 200-mg dose of doxycycline given within 72 hours after an I. scapularis tick bite can prevent the development of Lyme disease.

Adolescent↗

PubMed2001

Heart rate recovery: validation and methodologic issues.

OBJECTIVES: The goal of this study was to validate the prognostic value of the drop in heart rate (HR) after exercise, compare it to other test responses, evaluate its diagnostic value and clarify some of the methodologic issues surrounding its use. BACKGROUND: Studies have highlighted the value of a new prognostic feature of the treadmill test-rate of recovery of HR after exercise. These studies have had differing as well as controversial results and did not consider diagnostic test characteristics. METHODS: All patients were referred for evaluation of chest pain at two university-affiliated Veterans Affairs Medical Centers who underwent treadmill tests and coronary angiography between 1987 and 1999 as predicted after a mean seven years of follow-up. All-cause mortality was the end point for follow-up, and coronary angiography was the diagnostic gold standard. RESULTS: There were 2,193 male patients who had treadmill tests and coronary angiography. Heart rate recovery at 2 min after exercise outperformed other time points in prediction of death; a decrease of <22 beats/min had a hazard ratio of 2.6 (2.4 to 2.8 95% confidence interval). This new measurement was ranked similarly to traditional variables including age and metabolic equivalents but failed to have diagnostic power for discriminating those who had angiographic disease. CONCLUSIONS: Heart rate at 1 or 2 min of recovery has been validated as a prognostic measurement and should be recorded as part of all treadmill tests. This new measurement does not replace, but is supplemental to, established scores.

Adult↗

PubMed2001

Role of exercise in preventing and treating osteoporosis.

Bone mass at any time of life reflects the totality of events that have impinged on the skeleton to that point. For adults, these events include those that have influenced the acquisition of bone during years of growth, resulting in the achievement of skeletal maturity, or "peak bone mass," as well as those that have subsequently influenced bone losses. For each limb of this trajectory, physical activity has been implicated as a powerful and independent factor. This article reviews current evidence regarding the relation of habitual physical activity to bone acquisition and maintenance, the skeletal consequences of exercise training, and the clinical value of exercise for patients with skeletal frailty.

Adolescent↗

PubMed2001

A theoretical analysis of the contributions of remodeling space, mineralization, and bone balance to changes in bone mineral density during alendronate treatment.

In patients with osteoporosis, alendronate treatment causes an increase in bone mineral density (BMD) and a decrease in fracture incidence. Alendronate acts by changing the bone remodeling process. Changes in bone remodeling resulting in decreased remodeling space, increased bone balance per remodeling cycle, and increased mineralization (ash mass/bone mass) have all been associated with alendronate treatment. Understanding the relative contributions of these parameters to BMD increases could help predict the utility of long-term (>10 years) or intermittent treatment strategies, as well as treatment strategies in which another pharmaceutical is administered concurrently. We have developed a computer simulation of bone remodeling to compare the contributions of focal bone balance and mineralization on BMD by simulating alendronate treatment using a bone balance method (decreased remodeling space, increased focal bone balance, uniform bone mineralization) and a mineralization method (decreased remodeling space, neutral focal bone balance, varying bone mineralization). Although both methods are able to predict BMD increases caused by alendronate over short periods, our findings suggest that the mineralization method may be more descriptive of long-term alendronate treatment. This implies that mineralization may be a larger contributor to BMD changes caused by alendronate than the focal bone balance. Based on this finding we offer a hypothesis to describe how remodeling space, focal bone balance, and mineralization each contribute to alendronate-induced BMD changes. Future analyses with this method could be used to identify improved dosing regimens and to predict which osteoporosis treatments would best complement each other.

Alendronate↗

PubMed2001

Alpha-interferon maintenance treatment is associated with improved survival after high-dose treatment and autologous stem cell transplantation in patients with multiple myeloma: a retrospective registry study from the European Group for Blood and Marrow Transplantation (EBMT).

The purpose of this study was to evaluate the effect of alpha-IFN maintenance treatment after autologous stem cell transplantation (ASCT) for multiple myeloma in a retrospective registry analysis. 473 patients with multiple myeloma who received IFN maintenance treatment ASCT were compared with 419 patients who did not receive IFN-treatment. Patients who were evaluable for response and in complete or partial remission at 6 months after ASCT were eligible, after excluding patients with graft failure. Cox proportional hazards assumptions were checked and handled by stratification. The prognostic variables unevenly distributed between the two groups were statistically corrected for in the Cox analysis. 391 patients reached complete remission (CR) after ASCT (203 in the IFN group and 188 in the no-IFN group) and 501 were in partial remission (PR, IFN 270, no-IFN 231). Overall survival (OS) and progression-free survival (PFS) were significantly better in the IFN-group (OS, 78 vs 47 months, P = 0.007, and PFS, 29 vs 20 months, P = 0.006, respectively). The difference in OS and PFS was most strongly pronounced in the PR patients. 209 patients have died (IFN, 84; no-IFN, 125). Progressive myeloma was the cause of death in 94% of the IFN-treated patients and in 83% of the no-IFN group (P = NS). Thus, IFN maintenance treatment after ASCT was associated with better OS and PFS. Treatment seemed to be most beneficial in patients who did not achieve CR. The difference in median survival was as long as 2.5 years, and although part of this difference is attributable to differences in other prognostic factors, it might justify possible differences in quality-of-life due to adverse effects of interferon treatment.

Adolescent↗

PubMed2001

Combined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia.

PSC 833 (Valspodar) can reverse multidrug resistance (MDR) in patients with hematologic malignancies, but alters the pharmacokinetics of concomitant anticancer agents. A phase I, dose-finding study was initiated to define a safe and effective regimen of mitoxantrone, etoposide, and cytarabine (MEC) when administered with PSC 833 to patients with early relapsed or refractory acute myeloid leukemia (AML). Poor-prognosis AML patients refractory to first-line induction therapy or relapsing within 9 months of attaining complete remission (CR) were treated with cytarabine (1.0 g/m2/day), etoposide (30 mg/m2/day), and mitoxantrone at a dose of either 3.0 mg/m2/day (cohort 1) or 4.5 mg/m2/day (cohorts 2 and 3) for 6 days plus continuous-infusion PSC 833 (10 mg/kg/24 h with a 2.0 mg/kg loading dose) for 6 or 7 days each 21-day cycle. Patients achieving CR were given a 4-day MEC plus PSC 833 consolidation cycle. Twenty-three patients were enrolled (eight with primary refractory AML and 15 in relapse). Dose-limiting toxicity occurred in one of six patients in cohort 2 (grade 4 mucositis) and one of seven patients in cohort 3 (grade 4 hyperbilirubinemia). The maximum tolerated dose of mitoxantrone was defined as 4.5 mg/m2/day. Clinically significant grade 4 hyperbilirubinemia, possibly related to PSC 833, occurred in four patients. Hematologic toxicities were as expected in this patient population, but were not dose limiting. Mild to moderate cerebellar ataxia and paresthesia occurred in six (26%) and five (22%) patients, respectively, but were not dose limiting. Overall, six of 23 (26%) patients achieved CR, including five patients with demonstrated P-glycoprotein expression and/or function. The median overall survival was 4 months. All six patients with a CR were alive and four (17%) patients were disease free at 12 months. Blood levels of PSC 833 were well above the target level of 1000 ng/ml, a concentration that is known to reverse MDR in vitro. PSC 833 reduced the clearance of etoposide by approximately two-fold. No correlation was observed between the mitoxantrone or etoposide area under the curve and response. In conclusion, the MEC plus PSC 833 tested regimen was well tolerated and the 26% CR rate warrants further testing of this regimen in a randomized, phase III trial.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation.

The primary objective of this study was to determine the complete remission (CR) rate achieved with the FLAG (fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor) regimen in patients with relapsed or refractory acute myeloid leukaemia (AML) or de novo refractory anaemia with excess of blasts in transformation (RAEB-t). Secondary objectives were to evaluate survival and toxicity. Induction treatment consisted of between one and two courses of FLAG. Patients achieving CR received between one and two courses of consolidation treatment. Eighty-three of the 89 patients entering the study were eligible for assessment. CR rates were: 17 out of 21 (81%) in late relapse AML (Group 1), 13 out of 44 (30%) in early relapse/refractory AML (Group 2), and 10 out of 18 (56%) in de novo RAEB-t (Group 3). Thirty-four of the 40 responders (85%) achieved CR after one induction course. Median survival times were 1.4 years, 3 months and 1.6 years in Groups 1, 2 and 3 respectively. Other than myelosuppression, the FLAG regimen was not generally associated with clinically significant toxicity and was well tolerated by most patients including the elderly. The FLAG regimen offers a very effective alternative treatment for CR induction in poor prognosis adult patients with either relapsed or refractory AML or de novo RAEB-t. FLAG delivers high-dose treatment without increasing overall toxicity, an approach which is of particular value in older patients, who constitute the majority in these diseases. It is therefore an important advance in developing new treatment options for these patients.

Acute Disease↗