Biomedical subjects

Nancy Geller

Publications and source records attributed to Nancy Geller.

11 recordsLinked to original sources

PubMed2006

The effect of unrelated donor marrow transplantation on health-related quality of life: a report of the unrelated donor marrow transplantation trial (T-cell depletion trial).

The primary objective of this study was to compare health-related quality of life (HRQL) in adult patients undergoing either ex vivo T cell-depleted bone marrow transplantation or conventional marrow transplantation. Data on patients' HRQL were gathered as part of a multicenter randomized trial comparing the effect of ex vivo T-cell depletion versus methotrexate and cyclosporine immunosuppression on disease-free survival. HRQL assessments were conducted at baseline, day +100, 6 months, 1 year, and 3 years. There were no treatment arm differences 1 year after transplantation on the Functional Assessment of Cancer Therapy, Bone Marrow Transplantation, the Medical Outcomes Study Short-Form 36, and the Centers for Epidemiological Studies of Depression. The lack of treatment differences was robust across types of data analyses that took baseline functioning into account and that recognized the sensitivity of outcome measures to assumptions concerning missing data. The trajectory of recovery revealed an initial decrease in function and then a recovery to pretreatment levels that were similar for both treatment arms. Furthermore, the patients in both treatment groups returned to a functional level that approximated general US population norms. Even though the incidence of acute graft-versus-host disease was slightly higher in the conventional treatment arm, T-cell depletion did not differentially affect HRQL at 1 year after transplantation.

Adult↗

PubMed2006

Overcoming graft rejection in heavily transfused and allo-immunised patients with bone marrow failure syndromes using fludarabine-based haematopoietic cell transplantation.

Allogeneic haematopoietic cell transplantation (HCT) can cure a variety of non-malignant haematological disorders. Although transplant outcomes for selected patients with severe aplastic anaemia (SAA) and paroxysmal nocturnal haemoglobinuria (PNH) have improved, older age, allo-immunisation from transfusions, prior immunosuppressive therapy and a prolonged time from diagnosis to transplantation are associated with worse outcome. Because of its potent immunosuppressive effects, we investigated a fludarabine-based non-myeloablative conditioning regimen in patients with transfusion-dependent non-malignant haematological disorders at increased risk for graft rejection with conventional transplant conditioning. Twenty-six patients with transfusion dependent/anti-thymocyte globulin (ATG)-refractory SAA, PNH or pure red cell aplasia underwent HCT from a human leucocyte antigen (HLA)-compatible relative. Transplant conditioning consisted of cyclophosphamide (120 mg/kg) and fludarabine (125 mg/m2) with or without ATG. Ciclosporine, alone or combined with mycophenolate mofetil or methotrexate, was used as graft-versus-host disease (GVHD) prophylaxis. All patients achieved durable engraftment and transfusion-independence. Twenty-four of 26 patients are alive at a median of 21 months following transplantation. Although a high cumulative incidence of acute (65% grades II-IV, 54% grades III-IV) and chronic GVHD (56%) was observed, only one patient died from transplant-related causes (cumulative incidence 7%). These data show that HCT following fludarabine-based non-myeloablative conditioning results in durable engraftment and excellent survival in SAA and PNH patients at high risk for graft rejection.

Adolescent↗

PubMed2005

Clinical factors that influence response to treatment strategies in atrial fibrillation: the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.

BACKGROUND: The AFFIRM Study was a randomized multicenter comparison of 2 treatment strategies, rate-control versus rhythm-control, in high-risk patients with atrial fibrillation (AF). The primary outcome of the trial showed no overall difference in survival between strategies. However, there may be important patient subgroups for which there are identifiable differences in outcome with 1 of the 2 strategies. METHODS AND RESULTS: Subgroups that were prespecified for analysis from the main AFFIRM Study were age, sex, coronary artery disease (CAD), hypertension, congestive heart failure (CHF), left ventricular ejection fraction (LVEF), rhythm at randomization, first episode of AF, and duration of the qualifying episode of AF. Baseline characteristics were analyzed for each subgroup. Adjusted hazard ratios for each subgroup and for each stratum were generated using Cox models, and these models were used to determine whether treatment strategy affected overall survival differentially by subgroup. Adjusted survival was worse for patients > or =65 years and for patients with a history of CHF, CAD, or an abnormal LVEF. In the adjusted analyses, the effect of treatment strategy was similar within all of the prespecified subgroups. When each subgroup stratum was analyzed separately, patients > or =65 years and patients without a history of CHF had significantly better outcome with rate-control therapy (each P < .01). CONCLUSIONS: Overall, treatment effect for rate control versus rhythm control was the same within each subgroup. However, certain selected patient categories may have better survival with one particular strategy for management of AF.

Age Factors↗

PubMed2005

Engraftment syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation: incidence and effects on survival.

Engraftment syndrome (ES) encompasses a constellation of symptoms that occur during neutrophil recovery after both autologous and allogeneic hematopoietic stem cell transplantation (HCT). Although it is well characterized after conventional myeloablative procedures, limited data exist on this complication after nonmyeloablative allogeneic HCT. The clinical manifestations, incidence, and risk factors associated with ES were investigated in a consecutive series of patients undergoing cyclophosphamide/fludarabine-based nonmyeloablative allogeneic HCT from a related HLA-compatible donor. Fifteen (10%) of 149 patients (median age, 53 years; range, 27-66 years) developed ES; the onset of symptoms occurred at a median of 10 days (range, 3-14 days), and they consisted of fever (100%), cough (53%), diffuse pulmonary infiltrates (100%), rash (13%), and room air hypoxia (87%). ES was more likely to develop in patients who received empiric amphotericin formulations after transplant conditioning (Fisher exact test; P=.007). In a multivariate analysis, older patient age, female sex, and treatment with amphotericin were predictors for the development of ES. Intravenous methylprednisolone led to the rapid resolution of ES; however, transplant-related mortality was significantly higher (cumulative incidence, 49% versus 16%; P=.0005), and median survival was significantly shorter (168 versus 418 days; P=.005) in patients with ES compared with non-ES patients. In conclusion, ES occurs commonly after cyclophosphamide/fludarabine-based nonmyeloablative transplantation and responds rapidly to corticosteroid treatment, but it is associated with a higher risk of nonrelapse mortality and with shorter overall survival.

Adult↗

PubMed2004

Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study.

BACKGROUND: The AFFIRM Study showed that treatment of patients with atrial fibrillation and a high risk for stroke or death with a rhythm-control strategy offered no survival advantage over a rate-control strategy in an intention-to-treat analysis. This article reports an "on-treatment" analysis of the relationship of survival to cardiac rhythm and treatment as they changed over time. METHODS AND RESULTS: Modeling techniques were used to determine the relationships among survival, baseline clinical variables, and time-dependent variables. The following baseline variables were significantly associated with an increased risk of death: increasing age, coronary artery disease, congestive heart failure, diabetes, stroke or transient ischemic attack, smoking, left ventricular dysfunction, and mitral regurgitation. Among the time-dependent variables, the presence of sinus rhythm (SR) was associated with a lower risk of death, as was warfarin use. Antiarrhythmic drugs (AADs) were associated with increased mortality only after adjustment for the presence of SR. Consistent with the original intention-to-treat analysis, AADs were no longer associated with mortality when SR was removed from the model. CONCLUSIONS: Warfarin use improves survival. SR is either an important determinant of survival or a marker for other factors associated with survival that were not recorded, determined, or included in the survival model. Currently available AADs are not associated with improved survival, which suggests that any beneficial antiarrhythmic effects of AADs are offset by their adverse effects. If an effective method for maintaining SR with fewer adverse effects were available, it might be beneficial.

Adrenergic beta-Antagonists↗

PubMed2003

Prior chemotherapy and allograft CD34+ dose impact donor engraftment following nonmyeloablative allogeneic stem cell transplantation in patients with solid tumors.

Significant engraftment variability occurs among patients following nonmyeloablative hematopoietic cell transplantation. We analyzed the impact of multiple factors on donor myeloid and T-cell engraftment in 36 patients with metastatic tumors undergoing cyclophosphamide/fludarabine-based conditioning. Higher CD34(+) doses facilitated donor myeloid engraftment, while prior chemotherapy exposure facilitated both donor myeloid and T-cell engraftment. At day 30, median donor T-cell and myeloid chimerism was 98% and 76%, respectively, in those patients with prior chemotherapy versus 88% (P =.008) and 26% (P <.0001) in chemotherapy-naive patients. Donor myeloid chimerism at day 45 was predicted by prior chemotherapy exposure and the log(10) of the CD34(+) dose (adjusted coefficient of determination [R(2)] =.47; P <.0001), while chemotherapy alone impacted donor T-cell engraftment. Patients with prior chemotherapy were more likely to develop acute grades II to IV graft-versus-host disease (GVHD; 8/18) compared with chemotherapy-naive patients (2/18; P =.031). Thus, tailoring the intensity of nonmyeloablative conditioning based on prior chemotherapy exposure is an important consideration in trial design.

Adult↗

PubMed2003

Detecting acute coronary syndrome in the emergency department with cardiac magnetic resonance imaging.

BACKGROUND: Managing chest pain in the emergency department remains a challenge with current diagnostic strategies. We hypothesized that cardiac MRI could accurately identify patients with possible or probable acute coronary syndrome. METHODS AND RESULTS: The diagnostic performance of MRI was evaluated in a prospective study of 161 consecutive patients. Enrollment required 30 minutes of chest pain compatible with myocardial ischemia but an ECG not diagnostic of acute myocardial infarction. MRI was performed at rest within 12 hours of presentation and included perfusion, left ventricular function, and gadolinium-enhanced myocardial infarction detection. MRI was interpreted qualitatively but also analyzed quantitatively. The sensitivity and specificity, respectively, for detecting acute coronary syndrome were 84% and 85% by MRI, 80% and 61% by an abnormal ECG, 16% and 95% for strict ECG criteria for ischemia (ST depression or T-wave inversion), 40% and 97% for peak troponin-I, and 48% and 85% for a TIMI risk score > or =3. The MRI was more sensitive than strict ECG criteria for ischemia (P<0.001), peak troponin-I (P<0.001), and the TIMI risk score (P=0.004), and MRI was more specific than an abnormal ECG (P<0.001). Multivariate logistic regression analysis showed MRI was the strongest predictor of acute coronary syndrome and added diagnostic value over clinical parameters (P<0.001). CONCLUSIONS: Resting cardiac MRI exhibited diagnostic operating characteristics suitable for triage of patients with chest pain in the emergency department. Performed urgently to evaluate chest pain, MRI accurately detected a high fraction of patients with acute coronary syndrome, including patients with enzyme-negative unstable angina.

Acute Disease↗

PubMed2003

Lessons learned from the DIG trial.

The Digitalis Investigation Group (DIG) trial was the first large simple trial conducted by the National Heart, Lung, and Blood Institute in conjunction with the Department of Veterans Affairs. A large simple trial is a major undertaking. Simplification at the sites requires careful planning and discipline. Lessons learned from the DIG trial were: (1) keep a large simple trial very simple and keep all study procedures very simple; (2) ancillary studies are important and can complement a large simple trial but require careful advanced planning; (3) anticipate special needs when shipping study drugs internationally; (4) regional coordinating centers can be very useful; (5) recruit as many capable sites as possible; (6) provide research-inexperienced sites/investigators with extra help to obtain federalwide assurance statements from the Office for Human Research Protections and institutional review board approvals; (7) adequately reimburse sites for the work completed; (8) maintain investigator enthusiasm; (9) monitor the slow performers and sites with numerous personnel changes; (10) choose an endpoint that is easy to ascertain; (11) keep the trial simple for participants; and (12) plan early for closeout and for activities between the end of the trial and publication of results.

Canada↗

PubMed2003

Overview of the DIG trial.

Congestive heart failure is a major public health problem in the United States, Canada, and other Western countries. The Digitalis Investigation Group (DIG) trial was a randomized, double-blind placebo-controlled trial that evaluated the effects of digoxin on all-cause mortality and on hospitalization for heart failure in patients with heart failure and left ventricular ejection fraction < or =0.45 with normal sinus rhythm. It was designed as a large simple trial. There were 6800 patients entered into the main study over a 31.5-month recruitment period at 302 participating centers in the United States and Canada. All patients were followed for a minimum of 28 months. In order for this study to succeed, many groups had to work together successfully. In this supplement, we present practical aspects of organizing and conducting a large simple trial such as DIG.

Canada↗

PubMed2003

Industry, government, and academic panel discussion on multiple comparisons in a "real" phase three clinical trial.

A Food and Drug Administration (FDA)/Industry/Academic Panel Discussion on multiplicity aspects of a real Phase III clinical trial was held at the Third International Conference on Multiple Comparisons, August 6, 2002, in Bethesda, Maryland. The goal was to develop some consensus among industry, government, and academic statisticians concerning requirements and methods for multiplicity management in typical clinical trials. The session was tape-recorded; this article mostly comes from an edited transcript.

Clinical Trials, Phase III as Topic↗

PubMed2002

A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndrome.

Laboratory observations suggest that, in some myelodysplastic syndromes (MDS), immune mechanisms may contribute to the impaired blood cell production. Tumor necrosis factor alpha (TNF-alpha), a potent inhibitor of haematopoiesis, has been hypothesized to mediate suppressive effects in MDS: TNF-alpha levels are elevated and correlated with marrow apoptosis and cytopenia. Inhibition of TNF-alpha production using the soluble TNF receptor (Enbrel) has been successful in rheumatoid arthritis, and we have now applied the same principle to MDS. We determined spontaneous TNF-alpha production by marrow cells in MDS; TNF-alpha production was elevated (> mean + 2 x SD of controls) in > 1/3 of patients, but did not correlate with clinical parameters. Sixteen patients participated in a 3-month pilot study of Enbrel. The drug was well tolerated and 15 patients were evaluable. Of these, one became temporarily (14 weeks) transfusion independent. In another patient, absolute neutrophil count (ANC) rose from 0.5 x 10(9)/l to 0.84 x 10(9)/l. Serious infections were seen in two out of six neutropenic patients. Progression to refractory anaemia with excess blasts in transformation (RAEBt) or leukaemia was observed in three patients. When the effects of Enbrel on haematopoietic colony formation were studied, no significant increase was seen in MDS and there was no correlation with TNF-alpha levels. Although anti-TNF therapy with Enbrel was well tolerated at the dosages used in MDS, its efficacy as a single agent appears low.

Adult↗