Susan G. Fisher

Amiodarone in Patients with Congestive Heart Failure and Asymptomatic Ventricular Arrhythmia

BACKGROUND Asymptomatic ventricular arrhythmias in patients with congestive heart failure are associated with increased rates of overall mortality and sudden death. Amiodarone is now used widely to prevent ventricular tachycardia and fibrillation. We conducted a trial to determine whether amiodarone can reduce overall mortality in patients with congestive heart failure and asymptomatic ventricular arrhythmias. METHODS We used a double-blind, placebo-controlled protocol in which 674 patients with symptoms of congestive heart failure, cardiac enlargement, 10 or more premature ventricular contractions per hour, and a left ventricular ejection fraction of 40 percent or less were randomly assigned to receive amiodarone (336 patients) or placebo (338 patients). The primary end point was overall mortality, and the median follow-up was 45 months (range, 0 to 54). RESULTS There was no significant difference in overall mortality between the two treatment groups (P = 0.6). The two-year actuarial survival rate was 69.4 percent (95 percent confidence interval, 64.2 to 74.6) for the patients in the amiodarone group and 70.8 percent (95 percent confidence interval, 65.7 to 75.9) for those in the placebo group. At two years, the rate of sudden death was 15 percent in the amiodarone group and 19 percent in the placebo group (P = 0.43). There was a trend toward a reduction in overall mortality among the patients with nonischemic cardiomyopathy who received amiodarone (P = 0.07). Amiodarone was significantly more effective in suppressing ventricular arrhythmias and increased the left ventricular ejection fraction by 42 percent at two years. CONCLUSIONS Although amiodarone was effective in suppressing ventricular arrhythmias and improving ventricular function, it did not reduce the incidence of sudden death or prolong survival among patients with heart failure, except for a trend toward reduced mortality among those with nonischemic cardiomyopathy.

Increased Incidence of Lymphoproliferative Disorder after Immunosuppression with the Monoclonal Antibody OKT3 in Cardiac-Transplant Recipients

BACKGROUND A sudden increase in the incidence of post-transplantation lymphoproliferative disorder among the patients in our cardiac-transplantation program was temporally related to introduction of the immunosuppressive drug OKT3. This monoclonal antibody has come to be widely used in recent years both to prevent and to treat rejection after cardiac transplantation. METHODS In order to identify variables that predict the development of post-transplantation lymphoproliferative disorder, we analyzed retrospectively a series of 154 consecutive cardiac-transplant recipients at a single institution. Univariate analyses and multivariate analysis by logistic regression were performed. RESULTS Among 75 patients who did not receive OKT3, post-transplantation lymphoproliferative disorder developed in 1 (1.3 percent), as compared with 9 of 79 patients who received the drug (11.4 percent); the incidence among the OKT3-treated patients was ninefold higher (odds ratio, 9.5; 95 percent confidence interval, 1.6 to 54.7). According to multivariate analysis, the only factor significantly associated with the development of post-transplantation lymphoproliferative disorder was the use of OKT3 (P = 0.001). A significant increase in risk with increasing doses was also apparent: 4 of 65 patients who received a cumulative dose of 75 mg of OKT3 or less (6.2 percent) had post-transplantation lymphoproliferative disorder, whereas 5 of 14 patients who received more than 75 mg had the disorder (35.7 percent; P less than 0.001). CONCLUSION The addition of OKT3 to the immunosuppressive regimen increases the incidence of post-transplantation lymphoproliferative disorder after cardiac transplantation, and the risk increases sharply after cumulative doses greater than 75 mg. We suggest that the risks and benefits of prophylactic OKT3 administration be reassessed in the light of these findings, particularly since the value of prophylactic immunotherapy in cardiac-transplant recipients remains to be clearly established.

Plasma phospholipids identify antecedent memory impairment in older adults

Alzheimers disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels, structural and functional magnetic resonance imaging and the recent use of brain amyloid imaging or inflammaging, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimers disease with the required sensitivity and specificity. Herein, we describe our lipidomic approach to detecting preclinical Alzheimers disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimers disease within a 2–3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimers disease.

Spontaneous Conversion and Maintenance of Sinus Rhythm by Amiodarone in Patients With Heart Failure and Atrial Fibrillation Observations from the Veterans Affairs Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT)

BACKGROUND In a multicenter, double-blind, placebo-controlled study, the long-term effects of amiodarone on morbidity and mortality in patients with congestive heart failure (CHF) and atrial fibrillation (AF) were evaluated during a 4-year period. METHODS AND RESULTS Of 667 patients with CHF, 103 (15%) had AF at baseline. Of these, 51 were randomized to amiodarone and 52 to placebo. The group with sinus rhythm and the group in AF were comparable except for a higher proportion of AF in patients with nonischemic versus ischemic cardiomyopathy (41% versus 27%, P<0.005). The mean ventricular response (VR) during AF over 24 hours was reduced by amiodarone at 2 weeks (20%, P=0.001), at 6 months (18%, P=0.001), and at 12 months (16%, P=0.006). Maximal VR was reduced 22% (P=0.001) at 2 weeks, 19% (P=0.001) at 6 months, and 14% (P=0.001) at 12 months. Sixteen of 51 patients on amiodarone and 4 of 52 on placebo converted to sinus rhythm during the study (chi2=9.23, P=0.002). During follow-up, 11 of 268 patients in sinus rhythm on amiodarone at baseline and 22 of the 263 in sinus rhythm on placebo developed AF; the difference was significant (chi2=12.88, P=0.005). Analysis of total mortality during follow-up showed a significantly lower mortality rate (P=0. 04) in patients in AF at baseline who subsequently converted to sinus rhythm on amiodarone than in those who did not convert to sinus rhythm on the drug. CONCLUSIONS In patients with CHF, amiodarone has a significant potential to spontaneously convert patients in AF to sinus rhythm, with patients who convert having a lower mortality rate than those who do not. The drug prevented the development of new-onset AF and significantly reduced the VR in those with persistent AF.

Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma.

PURPOSE The CD20 B-lymphocyte surface antigen expressed by B-cell lymphomas is an attractive target for radioimmunotherapy, treatment using radiolabeled antibodies. We conducted a phase I dose-escalation trial to assess the toxicity, tumor targeting, and efficacy of nonmyeloablative doses of an anti-CD20 monoclonal antibody (anti-B1) labeled with iodine-131 (131I) in 34 patients with B-cell lymphoma who had failed chemotherapy. PATIENTS AND METHODS Patients were first given tracelabeled doses of 131I-labeled anti-B1 (15 to 20 mg, 5 mCi) to assess radiolabeled antibody biodistribution, and then a radioimmunotherapeutic dose (15 to 20 mg) labeled with a quantity of 131I that would deliver a specified centigray dose of whole-body radiation predicted by the tracer dose. Whole-body radiation doses were escalated from 25 to 85 cGy in sequential groups of patients in 10-cGy increments. To evaluate if radiolabeled antibody biodistribution could be optimized, initial patients were given one or two additional tracer doses on successive weeks, each dose preceded by an infusion of 135 mg of unlabeled anti-B1 one week and 685 mg the next. The unlabeled antibody dose resulting in the most optimal tracer biodistribution was also given before the radioimmunotherapeutic dose. Later patients were given a single tracer dose and radioimmunotherapeutic dose preceded by infusion of 685 mg of unlabeled anti-B1. RESULTS Treatment was well tolerated. Hematologic toxicity was dose-limiting, and 75 cGy was established as the maximally tolerated whole-body radiation dose. Twenty-eight patients received radioimmunotherapeutic doses of 34 to 161 mCi, resulting in complete remission in 14 patients and a partial response in eight. All 13 patients with low-grade lymphoma responded, and 10 achieved a complete remission. Six of eight patients with transformed lymphoma responded. Thirteen of 19 patients whose disease was resistant to their last course of chemotherapy and all patients with chemotherapy-sensitive disease responded. The median duration of complete remission exceeds 16.5 months. Six patients remain in complete remission 16 to 31 months after treatment. CONCLUSION Nonmyeloablative radioimmunotherapy with 131I-anti-B1 is associated with a high rate of durable remissions in patients with B-cell lymphoma refractory to chemotherapy.

American Society of Clinical Oncology Clinical Practice Guideline for the Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer

PURPOSE To develop a clinical practice guideline for treatment of laryngeal cancer with the intent of preserving the larynx (either the organ itself or its function). This guideline is intended for use by oncologists in the care of patients outside of clinical trials. METHODS A multidisciplinary Expert Panel determined the clinical management questions to be addressed and reviewed the literature available through November 2005, with emphasis given to randomized controlled trials of site-specific disease. Survival, rate of larynx preservation, and toxicities were the principal outcomes assessed. The guideline underwent internal review and approval by the Panel, as well as external review by additional experts, members of the American Society of Clinical Oncology (ASCO) Health Services Committee, and the ASCO Board of Directors. RESULTS Evidence supports the use of larynx-preservation approaches for appropriately selected patients without a compromise in survival; however, no larynx-preservation approach offers a survival advantage compared with total laryngectomy and adjuvant therapy with rehabilitation as indicated. RECOMMENDATIONS All patients with T1 or T2 laryngeal cancer, with rare exception, should be treated initially with intent to preserve the larynx. For most patients with T3 or T4 disease without tumor invasion through cartilage into soft tissues, a larynx-preservation approach is an appropriate, standard treatment option, and concurrent chemoradiotherapy therapy is the most widely applicable approach. To ensure an optimum outcome, special expertise and a multidisciplinary team are necessary, and the team should fully discuss with the patient the advantages and disadvantages of larynx-preservation options compared with treatments that include total laryngectomy.

The epidemiology of non-Hodgkin's lymphoma

The incidence of non-Hodgkins lymphoma (NHL) has doubled over the past two decades in the US and most other westernized countries. While improved cancer reporting, changes in lymphoma classification, and increases in AIDS-associated lymphomas have contributed to the startling escalation of disease incidence, these factors are estimated to account for only about 50% of the increase in observed incidence. The elucidation of etiologic factors and their mechanistic role in the pathogenesis of this malignancy are critical to advancements in disease prevention and treatment. Current evidence suggests that factors/conditions that precipitate either chronic antigenic stimulation or immunosuppression may provide a preferential milieu for development of NHL. High rates of lymphoma have been observed among individuals with autoimmune disease, organ transplants, and primary or acquired immunodeficiencies. Ultraviolet radiation, previously demonstrated to have an immunosuppressive effect, has also been suggested as a possible risk factor for NHL. Several pathogens have been linked to the risk of lymphoma, including Epstein–Barr virus, human immunodeficiency virus, human T-cell lymphotropic virus-1, Helicobacter pylori, hepatitis C, and simian virus 40. Whether these microbes are responsible for specific genetic mutations that initiate tumor growth, antigenic stimulation leading to B-cell proliferation, and increased potential of random cell replication errors, or immunosuppression, which thereby promotes tumor growth, has not been clearly delineated. Other exogenous factors which have been implicated in lymphomagenesis are chemicals and agricultural exposures, hair dyes, and blood transfusions. We must build on our current knowledge regarding the etiology of NHL in order that prevention, treatment, and ultimately, cure of this malignancy becomes a reality.

Risk of second primary cancer in the contralateral breast in women treated for early-stage breast cancer: A population-based study

PURPOSE To study the potential risk factors, including radiotherapy (RT) for contralateral breast cancer (CBC), in patients treated for early-stage breast cancer. METHODS AND MATERIALS The Surveillance, Epidemiology, and End Results database (1973-1996) was used to study the incidence of CBC after breast cancer. The Cox proportional hazards regression model was used to estimate the relative risk (RR) of CBC, with adjustment for confounders, including age, race, histologic subtype, and use of RT. Information on the use of hormonal therapy and chemotherapy was not available in the Surveillance, Epidemiology, and End Results database. RESULTS A CBC was documented in 5679 (4.2%) of the 134501 localized invasive or intraductal breast cancer patients surviving at least 3 months. The 10- and 20-year actuarial rate of CBC was 6.1% and 12%, respectively. In multivariate analysis, medullary carcinoma (RR = 1.18, 95% confidence interval [CI] 1.02-1.37), black race (RR = 1.20, 95% CI 1.08-1.33), and age >55 years at initial diagnosis (RR = 1.15, 95% CI 1.08-1.22) were associated with increased CBC risk. A total of 1234 (3.3%) of 37,379 patients who received RT developed CBC, and 4445 (4.6%) of 97122 patients who did not receive RT developed CBC. Overall, RT was not associated with an increased risk of CBC (RR = 1.04, 95% CI 0.97-1.10) in multivariate analysis. The CBC risk associated with RT varied substantially with the length of follow-up. During the first 5 years of follow-up, RT was not associated with an increased CBC risk (age-adjusted RR = 0.96, 95% CI 0.88-1.04). For patients surviving for >5 years, RT was associated with a 14% increase in CBC risk (RR = 1.14, 95% CI 1.03-1.26). The increased CBC risk with RT was evident in patients aged <45 years (RR = 1.32, p = 0.01) and >55 years (RR = 1.15, p = 0.04) at initial diagnosis. The 5-, 10-, 15-, and 20-year actuarial rate of CBC was 2.9%, 6.5%, 10.2%, and 13.4%, respectively, for patients with RT; the corresponding rates were 3.0%, 6.0%, 8.9%, and 11.8% for patients without RT. The absolute increase in CBC risk associated with RT was 0.5%, 1.3%, and 1.6% in the 10-, 15-, and 20-year actuarial rate, respectively. CONCLUSION CBC is not uncommon after breast cancer, especially for certain subsets of patients. RT was associated with a very small increased long-term CBC risk. This minimal increase in CBC risk should not affect clinical decision-making in treatment selection for patients with localized invasive breast cancer or ductal carcinoma in situ. Unnecessary radiation exposure to the contralateral breast should be avoided for all patients with early-stage breast cancer.

Cumulative Antibiotic Exposures Over Time and the Risk of Clostridium difficile Infection

BACKGROUND Clostridium difficile infection (CDI) is a major cause of hospital-acquired diarrhea and is most commonly associated with changes in normal intestinal flora caused by administration of antibiotics. Few studies have examined the risk of CDI associated with total dose, duration, or number of antibiotics while taking into account the complex changes in exposures over time. METHODS A retrospective cohort study conducted from 1 January to 31 December 2005 among hospitalized patients 18 years or older receiving 2 or more days of antibiotics. RESULTS The study identified 10,154 hospitalizations for 7,792 unique patients and 241 cases of CDI, defined as the detection of C. difficile toxin in a diarrheal stool sample within 60 days of discharge. We observed dose-dependent increases in the risk of CDI associated with increasing cumulative dose, number of antibiotics, and days of antibiotic exposure. Compared to patients who received only 1 antibiotic, the adjusted hazard ratios (HRs) for those who received 2, 3 or 4, or 5 or more antibiotics were 2.5 (95% confidence interval [CI] 1.6-4.0), 3.3 (CI 2.2-5.2), and 9.6 (CI 6.1-15.1), respectively. The receipt of fluoroquinolones was associated with an increased risk of CDI, while metronidazole was associated with reduced risk. CONCLUSIONS Cumulative antibiotic exposures appear to be associated with the risk of CDI. Antimicrobial stewardship programs that focus on the overall reduction of total dose as well as number and days of antibiotic exposure and the substitution of high-risk antibiotic classes for lower-risk alternatives may reduce the incidence of hospital-acquired CDI.

Effect of Amiodarone on Clinical Status and Left Ventricular Function in Patients With Congestive Heart Failure

BACKGROUND Although trials of amiodarone therapy in patients with congestive heart failure have produced discordant results with regard to effects on survival, most studies have reported a significant rise in left ventricular ejection fraction during long-term therapy. In the present study, we determined whether this increase in ejection fraction is associated with an improvement in the symptoms and/or physical findings of heart failure or a reduction in the number of hospitalizations for heart failure. METHODS AND RESULTS In the Department of Veterans Affairs cooperative study of amiodarone in congestive heart failure, 674 patients with New York Heart Association class II through IV symptoms and ejection fractions of < or = 40% were treated with amiodarone or placebo for a median of 45 months in a randomized, double-blind, placebo-controlled protocol. Clinical assessments and radionuclide ejection fraction were performed at baseline and after 6, 12, and 24 months. Compared with the placebo group, ejection fraction increased more in the amiodarone group at each time point (8.1 +/- 10.2% [mean +/- SD] versus 2.6 +/- 7.9% at 6 months, 8.0 +/- 10.9% versus 2.7 +/- 8.0% at 12 months, and 8.8 +/- 10.1% versus 1.9 +/- 9.4% after 24 months, all P < .001). However, this difference was not associated with greater clinical improvement, lesser diuretic requirements, or fewer hospitalizations for heart failure (11.1% for amiodarone and 13.6% for placebo group; overall relative risk in the amiodarone group, 0.81 [95% CI, 0.56 to 1.10], P = .18). Of note is the trend toward a reduction in the combined end point of hospitalizations and cardiac deaths (relative risk, 0.82 [CI, 0.65 to 1.03], P = .08), which was significant in patients with nonischemic etiology (relative risk, 0.56 [CI, 0.36 to 0.87], P = .01) and absent in the ischemic group (relative risk, 0.95). CONCLUSIONS Although amiodarone therapy resulted in a substantial increase in left ventricular ejection fraction in patients with congestive heart failure, this was not associated with clinical benefit in the population as a whole. The substantial reduction in the combined end point of cardiac death plus hospitalizations for heart failure in the nonischemic group suggests possible benefit in these patients.