Relationship between cyclosporine area-under-the curve and acute graft versus host disease in pediatric patients undergoing hematopoietic stem cell transplant: A prospective, multicenter study.

Traditionally in hematopoietic stem cell transplant (HSCT), cyclosporine doses are individualized using cyclosporine trough concentrations (C0) while area under the concentration vs time curve (AUC) is used in solid organ transplant. AUC potentially has an important relationship with the development of acute graft-versus-host-disease (aGVHD). We conducted a prospective study to describe the relationship between severe (grade III-IV) aGVHD and cyclosporine AUC in pediatric HSCT recipients. Pediatric patients who underwent allogeneic myeloablative HSCT and scheduled to receive cyclosporine for aGVHD prophylaxis participated in this multicenter study. Cyclosporine doses were adjusted based on C0 according to each center's standard of care. Cyclosporine AUC was determined weekly until neutrophil engraftment or Day +42, whichever was later. Associations between severe aGVHD and cyclosporine AUC and other patient and treatment-related factors were evaluated. Of the 110 children enrolled, 97 were evaluable. Thirty-seven (38%) children developed aGVHD; 13 (13.4%) had severe aGVHD. On univariate analysis, there was no association between severe aGVHD and cyclosporine AUC at any time point before engraftment. Future research should focus on refinement of C0 targets for cyclosporine therapeutic drug monitoring in HSCT.

What distinguishes the Gordon Research Conference on Oceans and Human Health? A retrospective 2008-2012.

This piece is being submitted as a short commentary for the special edition on Oceans and Human Health (OHH). It is written from the perspective of a student who has attended all three biennial Gordon Research Conferences and Seminars on OHH beginning in 2008.

Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission.

Approximately 10% of children with ALL present at diagnosis with VHR for relapse if treated with chemotherapy alone. They may benefit from allogeneic HSCT in CR1. We have reviewed the outcome of this population in our institution. Forty-three patients (median age: 8.9 yr) with VHR ALL in CR1 underwent HSCT from October 1994 to April 2006. VHR features included Philadelphia chromosome (n = 17), induction failure (n = 9), hypodiploidy (n = 6), MLL gene rearrangement (n = 5), and others (n = 6). All patients received TBI (1200 cGy) with either CY and/or etoposide. Stem cell source was unrelated (n = 24) and related (n = 19). Incidence of grade III-IV acute GVHD and chronic extensive GVHD were 25% and 16%, respectively. Twelve patients relapsed (eight received related HSCT). Eleven patients died due to transplant-related mortality (eight received unrelated HSCT). For a median follow up of 39 months (range 11-110), the event free survival and OS were 0.49 (95% CI: 0.31-0.67) and 0.53 (CI: 0.44-0.71), respectively. Outcomes of children with VHR ALL receiving HSCT in CR1 remain unsatisfactory. Relapse, mainly after related HSCT, and TRM, mainly after unrelated HSCT, continue to be major problems.

Allogeneic hematopoietic stem cell transplantation of patients with FA and high risk features using fludarabine without radiation.

Several factors unique to Fanconi anemia (FA) limit the success of allogeneic hematopoietic stem cell transplantation (HSCT) in this population. In this report, we describe a multi-center pilot study of five consecutive FA patients with high-risk features for transplant prepared with fludarabine, without radiation. Four patients engrafted quickly, experienced minimal toxicity and are well at 43-65 months post-transplant. One patient had a C-mismatched unrelated donor transplant and had unsustained engraftment. This fludarabine based regimen without radiation was safe and effective for four high-risk patients, suggesting that eliminating radiation should be further studied as an approach to HSCT in children with FA.

Cyclosporine-induced pain syndrome in a child undergoing hematopoietic stem cell transplant.

OBJECTIVE: To report a case of calcineurin-induced pain syndrome (CIPS) in a child undergoing his second hematopoietic stem cell transplant (HSCT). CASE SUMMARY: A 6.1-year-old child received cyclosporine and methotrexate for acute graft-versus-host disease (aGVHD) prophylaxis after his first HSCT for acute myeloblastic leukemia. Amlodipine was given for the treatment of hypertension. Symptoms of CIPS were not observed. After the second HSCT at the age of 6.7 years, the child received cyclosporine (target trough whole blood cyclosporine concentration range 150-200 microg/L), starting on day -3, and mycophenolate mofetil for aGVHD prophylaxis. With the first cyclosporine dose, the patient complained of leg pain that was most severe during the cyclosporine infusion. Analgesic agents and a change from intravenous to oral administration of cyclosporine were ineffective in controlling the pain. Magnetic resonance imaging findings on day 10 showed periosteal soft tissue changes and mild bone marrow edema of the femora and tibiae. Tacrolimus was substituted for cyclosporine on day 20; on day 21 amlodipine was initiated to manage hypertension. Trough whole blood tacrolimus concentrations ranged from 1.7 to 6.2 microg/L. Pain was reduced in severity by day 29 and completely resolved once tacrolimus was discontinued on day 42. In this case, CIPS was considered to be probably associated with cyclosporine according to the Naranjo probability scale. DISCUSSION: CIPS is hypothesized to result from calcineurin-induced vascular changes that disturb bone perfusion and permeability, leading to intraosseous vasoconstriction and bone marrow edema. In our patient, symptoms were most acute during the infusion, when whole blood cyclosporine concentrations were likely to be the highest. Our patient's symptoms were resolved when tacrolimus was substituted for cyclosporine and amlodipine was initiated. CONCLUSIONS: Interventions aimed at reducing pain associated with CIPS may include the initiation of calcium-channel blocker therapy and conversion to an alternative calcineurin inhibitor.

Evidence-Based Valuation in Oncology:: Lessons Learned from a Case Study.

BACKGROUND: Value demonstration in health care remains a challenge. This paper examines traditional approaches to pricing and the evolution of value-based pricing (VBP), and proposes a new framework for evidence-based valuation (EBV). The main objective of EBV is to estimate the value-based pricing range for the new medicine, identify key product attributes that drive value as perceived by various stakeholders, and then elucidate the requisite evidence to support those value claims. METHODS: EBV centers on a structured framework for estimating a drug's price based on its perceived value to various stakeholders. The EBV framework consists of identifying key value attributes that drive adoption of a drug in a given therapeutic area; gaining insights into stakeholder value considerations and evidence requirements; and quantifying stakeholders' perceptions of specific value attributes within pricing premiums. RESULTS: An example demonstrates the application of the EBV framework in a simplified manner for 3 drugs indicated for renal cell carcinoma, 3 drugs for prostate cancer, and 1 drug for melanoma. HTAs, published trial results, and publications archived in PubMed between 2005 and 2013 were analyzed to identify key value attributes. The following 5 attributes were considered: overall survival (OS), progression-free survival (PFS), population size, trial comparator, and adverse events. CONCLUSIONS: The method described offers a means to appraise pharmaceuticals in an environment increasingly focused on evidence-based medicine and value-based health care.

Synthesis and characterisation of α-carboxynitrobenzyl photocaged l-aspartates for applications in time-resolved structural biology.

We report a new synthetic route to a series of α-carboxynitrobenzyl photocaged l-aspartates for application in time-resolved structural biology. The resulting compounds were characterised in terms of UV/Vis absorption properties, aqueous solubility and stability, and photocleavage rates (τ = µs to ms) and quantum yields (φ = 0.05 to 0.14).

Inferior outcomes for overweight children undergoing allogeneic stem cell transplantation.

This retrospective cohort study aimed at determining whether overweight children undergoing allogeneic stem cell transplantation (SCT) had inferior overall survival compared with children who were not overweight. Children >/=2 years of age who received allogeneic SCT were included. Overweight was defined as a body mass index >/= 95th percentile; 54/325 (17%) children were overweight. Overall survival at 5 years was significantly inferior at 46.6 +/- 7.3% in the overweight group compared with 59.5 +/- 3.2% in the non-overweight group (P = 0.02). Our study demonstrated that overweight children who undergo allogeneic SCT had inferior survival compared with children who were not overweight.

Direct costs of blindness experienced by patients enrolled in managed care.

PURPOSE: To evaluate total and condition-related charges incurred by blind patients in a managed care population in the United States and compare total charges with those of a matched nonblind cohort. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with blindness (N = 10 796) and a 1:1 matched cohort of nonblind patients were selected from a managed care claims database. All study subjects were required to be > or =18 years old at diagnosis (blind patients) or enrollment (nonblind patients) and to have had > or =1 years of continuous follow-up. METHODS: Total and pharmacy-related direct medical charges in the first year of follow-up were calculated for both blind and nonblind cohorts. Among blind patients, condition-related charges, charge per treated person, and charge breakdown by age group were calculated. For patients with follow-up extending past 1 year, total charges (both cohorts) and condition-related charges (blind cohort only) were assessed and annualized. Mean and median charges were assessed for blind and nonblind patients within each stratum of matched covariates; a multivariate linear regression assessed the statistical significance of the difference in charges between the 2 cohorts. MAIN OUTCOME MEASURES: Total health care charges in the first year of follow-up and condition-related health care charges in the first year of follow-up for blind patients. RESULTS: For the blind population (mean age, 52 years [standard deviation (SD), 17.5]), the total mean and median health care charges per person in the first year were $20,677 (SD, $48,835) and $6854, respectively. Total mean and median health care charges per nonblind patient in the first year were $13,321 (SD, $40,059) and $3778, respectively. Condition-related charges among blind patients were substantially lower than total charges, with mean and median charges per person of $4565 (SD, $17,472) and $371, respectively. After adjusting for covariates, blind patients had significantly higher total health care charges in the first year of follow-up than nonblind patients (P<0.0001). Costs of the blind did not differ substantially from costs of the normally sighted in subsequent years of follow-up. CONCLUSION: This study demonstrates the substantial direct cost burden of blindness during the first year of follow-up in a managed care population.

Health care charges for patients with ocular hypertension or primary open-angle glaucoma.

OBJECTIVES: To determine the total and condition-related direct health care charges of patients with ocular hypertension (OH) or primary open-angle glaucoma (POAG) and identify factors that affect these charges. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with OH (n = 36 767) and POAG (n = 72 412) with > or =1 year of continuous enrollment during calendar years 1998 through 2005 in a nationally representative, multimanaged health plan database (PharMetrics). METHODS: First year total health care and condition-related charges were calculated. Subsequently multivariate linear regression models determined the impact of ophthalmic condition (OH or POAG), age, index year, gender, geographic region, payer mix, product type, treatment with glaucoma medication, ocular comorbidities, and systemic comorbidities on these charges. MAIN OUTCOME MEASURES: Per-person per year first-year total health care and ocular condition-related charges in United States dollars, adjusted for multiple covariates. RESULTS: Patients with POAG had significantly higher adjusted total and condition-related health care charges during the first year of follow-up than patients with OH in multivariable analysis ($2070 vs. $1990, P<0.0001 and $556 vs. $322 P<0.0001, respectively). Females and older patients had higher total health care charges compared with males and younger patients ($586 or 28.3% more; P<0.0001 and $27 per year or 0.8% per year more; P<0.0001, respectively). However, neither gender nor age were strong determinants of condition-related charges (P = 0.13 and P = 0.052, respectively). Index year, region, payer, and product types significantly dictated both total and disease-related charges. Patients with ocular comorbid conditions, including cataracts, cataract surgery, diabetic retinopathy, and blindness, had significantly higher total and condition-related health care charges than patients without these conditions (P<0.0001). CONCLUSION: Total and condition-related health care charges are considerable for patients with OH and POAG. These data identify several factors that dictate these charges.

Anemia, transfusions and hospital outcomes among critically ill patients on prolonged acute mechanical ventilation: a retrospective cohort study.

INTRODUCTION: Patients requiring prolonged acute mechanical ventilation (PAMV) represent one-third of those who need mechanical ventilation, but they utilize two-thirds of hospital resources devoted to mechanical ventilation. Measures are needed to optimize the efficiency of care in this population. Both duration of intensive care unit stay and mechanical ventilation are associated with anemia and increased rates of packed red blood cell (pRBC) transfusion. We hypothesized that transfusions among patients receiving PAMV are common and associated with worsened clinical and economic outcomes. METHODS: A retrospective analysis of a large integrated claims database covering a 5-year period (January 2000 to December 2005) was conducted in adult patients receiving PAMV (mechanical ventilation for >/= 96 hours). The incidence of pRBC transfusions was examined as the main exposure variable, and hospital mortality served as the primary outome, with hospital length of stay and costs being secondary outcomes. RESULTS: The study cohort included 4,344 hospitalized patients receiving PAMV (55% male, mean age 61.5 +/- 16.4 years). Although hemoglobin level upon admission was above 10 g/dl in 75% of patients, 67% (n = 2,912) received at least one transfusion, with a mean of 9.1 +/- 12.0 units of pRBCs transfused per patient over the course of hospitalization. In regression models adjusting for confounders, exposure to pRBCs was associated with a 21% increase in the risk for hospital death (95% confidence interval [CI] = 1.00 to 1.48), and marginal increases in length of stay (6.3 days, 95% CI = 5.1 to 7.6) and cost ($48,972, 95% CI = $45,581 to $52,478). CONCLUSION: Patients receiving PAMV are at high likelihood of being transfused with multiple units of blood at relatively high hemoglobin levels. Transfusions independently contribute to increased risk for hospital death, length of stay, and costs. Reducing exposure of PAMV patients to blood may represent an attractive target for efforts to improve quality and efficiency of health care delivery in this population.

Contraceptive and noncontraceptive benefits of the LNG-IUS in a vertically integrated HMO.

BACKGROUND: The study was conducted to assess outcomes among women using the levonorgestrel-releasing intrauterine system (LNG-IUS). STUDY DESIGN: The data were collected via a retrospective claims database analysis of 152 women. Two nested cohorts were further distinguished based on length of follow-up: two and three continuous years (n=73 and n=29, respectively). RESULTS: Over 90% had a single insertion, and fewer than 4% experienced an LNG-IUS-related complication. Thirteen percent of women experienced menorrhagia in the year preceding insertion; this figure dropped to 12.5%, 1.2% and 0% in the 1, 2 and 3 years postinsertion. Mean number of gynecology-related visits decreased from four to two in the overall cohort, from seven to four in the cohort with 2 years of follow-up and from nine to four in the cohort with 3 years of follow-up. CONCLUSION: LNG-IUS use prevented pregnancy in all patients and was associated with decreased vaginal bleeding starting in the second year postinsertion.

Acute exposure to TiO2 nanoparticles produces minimal apparent effects on oyster, Crassostrea virginica (Gmelin), hemocytes.

The response of oyster (Crassostrea virginica) hemocytes was studied following exposure to anatase nanoparticles (ca. 7.4nm), surface-coated rutile nanocomposites (UV-Titan M212, ca. 86nm) and bulk titanium dioxide (TiO2) particles (anatase and rutile crystalline forms; 0.4-0.5µm). Hemocytes were collected from oysters and exposed to one of the four particle types at concentrations of 0.1, 0.5, and 1.0mg/L under dark and environmentally-relevant light conditions for periods of two and four hours. Hemocyte mortality, phagocytosis, and reactive oxygen species (ROS) production were then evaluated using flow-cytometric assays. Bulk and nanoparticulate TiO2 had little effect on viability of oyster hemocytes or on production of ROS. Significant changes in phagocytosis occurred after exposure to anatase nanoparticles for 4h under dark conditions, and UV-Titan for 2h under light conditions. Results demonstrate that TiO2 particles (bulk or nanoscale) produce minimal effects on hemocyte biomarkers examined following acute, in vitro exposures.

Radiation therapy, cardiac risk factors, and cardiac toxicity in early-stage breast cancer patients.

PURPOSE: The benefits of adjuvant radiation therapy (RT) for breast cancer may be counterbalanced by the risk of cardiac toxicity. We studied the cardiac effects of RT and the impact of pre-existing cardiac risk factors (CRFs) in a population-based sample of older patients with breast cancer. METHODS AND MATERIALS: In the Surveillance, Epidemiology and End-Results (SEER)-Medicare database of women > or = 65 years diagnosed with Stages I to III breast cancer from January 1, 1992 to December 31, 2000, we used multivariable logistic regression to model the associations of demographic and clinical variables with postmastectomy and postlumpectomy RT. Using Cox proportional hazards regression, we then modeled the association between treatment and myocardial infarction (MI) and ischemia in the 10 or more years after diagnosis, taking the predictors of treatment into account. RESULTS: Among 48,353 women with breast cancer; 19,897 (42%) were treated with lumpectomy and 26,534 (55%) with mastectomy; the remainder had unknown surgery type (3%). Receipt of RT was associated with later year of diagnosis, younger age, fewer comorbidities, nonrural residence, and chemotherapy. Postlumpectomy RT was also associated with white ethnicity and no prior history of heart disease (HD). The RT did not increase the risk of MI. Presence of MI was associated with age, African American ethnicity, advanced stage, nonrural residence, more than one comorbid condition, a hormone receptor-negative tumor, CRFs and HD. Among patients who received RT, tumor laterality was not associated with MI outcome. The effect of RT on the heart was not influenced by HD or CRFs. CONCLUSION: It appears unlikely that RT would increase the risk of MI in elderly women with breast cancer, regardless of type of surgery, tumor laterality, or history of CRFs or HD, for at least 10 years.

Cost of patients with primary open-angle glaucoma: a retrospective study of commercial insurance claims data.

PURPOSE: Primary open-angle glaucoma (POAG) poses a large burden on eye care resources in the United States. We evaluated the total health care and POAG-specific charges (both pharmacy and nonpharmacy) incurred by patients with POAG using a longitudinal U.S. commercial insurance claims database to determine the relative magnitude of glaucoma care charges to overall health care charges for those patients with glaucoma. DESIGN: Retrospective cohort design. PARTICIPANTS: Sixty-four thousand three hundred eighty patients with POAG were identified. METHODS: Patients with POAG were selected (International Classification of Diseases, 9th Revision code 365.11 on at least 2 encounters) from a managed care claims database. Total health care and POAG-specific charges were calculated. Component charges (pharmacy and nonpharmacy) also were evaluated and the charge per treated person was calculated. MAIN OUTCOME MEASURE: Health care charges. RESULTS: The mean total health care charges per person in the first year after initial entry into the database with POAG were $13,404 (standard deviation [SD], $33,987), with a median charge of $5403. The mean POAG-specific charge per person was $1570 (SD, $3428), with a median charge of $840. Pharmacy charges were 25% of the POAG-specific charges. The POAG-specific charges in subsequent years after the initial year decreased by 7% per year, whereas the total health care mean charge increased by 39% per year. Patients aged 65 years and older had significantly higher mean charges for both total health care charges ($16,759 vs. $11,651; P<0.0001) and POAG-specific charges ($1624 vs. $1542; P = 0.0049), for an age-related increase of 44% for total charges and 5% for POAG-specific charges. Overall, POAG-specific mean charges represented 12% of total mean charges in the first year and 8% of total overall mean charges in subsequent years. CONCLUSIONS: There is a substantial cost burden associated with POAG in a population with commercial insurance, and most of these charges are not pharmacy related.

The impact of glaucoma coding in a large claims database.

PURPOSE: Coding variation and its impact on identified populations is a major concern in database analyses. We assessed potential differences in demographics and healthcare charges among patients with open-angle glaucoma identified through different International Classification of Diseases, Ninth Revision (ICD-9) coding algorithms. DESIGN: Retrospective database analysis. METHODS: Three glaucoma cohorts were identified based on hierarchical inclusion of patients with >/=2 glaucoma ICD-9 codes (PharMetrics, Inc, Watertown, Massachusetts, USA, 1998 to 2003). Descriptive statistics and healthcare charges were assessed for each cohort. RESULTS: The three cohorts included 64,380, 14,705, and 4,225 unique patients each. Although significant differences in age, gender, region, payer type, product type, and medical comorbidities existed among the three cohorts, these differences had little impact on resource consumption when the cohorts were combined, given the smaller number of patients outside of the primary cohort. CONCLUSIONS: Glaucoma coding variation in administrative data sets has limited impact on analyses of resource consumption among open-angle glaucoma patients.

Imaging the complications of bone marrow transplantation in children.

Bone marrow transplantation is frequently performed to restore hematologic and immunologic competence after chemotherapy and radiation therapy for a range of childhood malignancies, as well as to treat various congenital conditions in which hematologic and immunologic functions are depressed or absent. Potentially devastating complications may occur during the pre-engraftment period after bone marrow transplantation, when marrow aplasia may supervene for several weeks until engraftment occurs, as well as during the post-engraftment period (the 3 months after engraftment) and in subsequent months and years. Complications of bone marrow transplantation may be classified either according to the time interval between transplantation and the occurrence of the complication or according to the organ system affected. The range of complications that may affect the central nervous system and the rest of the body may be detected with ultrasonography, computed tomography, and magnetic resonance imaging. Neurologic, paranasal sinus, pulmonary, and abdominopelvic complications all may be seen after bone marrow transplantation. Graft-versus-host disease and lymphoproliferative disorders also may occur. The increasing use of bone marrow transplantation mandates that the radiologist be familiar with the full range of potential complications and their imaging appearances.

Glaucoma in the United States and europe: predicting costs and surgical rates based upon stage of disease.

PURPOSE: Primary open-angle glaucoma is a significant health-economic burden in both the United States and Europe that is likely to increase. This study compared treatment patterns and cost among patients with primary open-angle glaucoma in these locations. METHODS: Retrospective medical chart reviews were conducted in the United States (1990 to 2002) and Europe (1995 to 2003). A total sample of 151 US charts and 194 European charts was studied, and patients were assigned a baseline intraocular pressure (IOP) and baseline stage, using a 6-stage visual functional glaucoma staging algorithm. Resource utilization and direct costs were assessed by stage of disease using publicly available United States and European costs. Cox Proportional Hazards modeling were used to examine covariates predicting glaucoma surgery. Total cost was predicted, adjusting for covariates using Generalized Linear Models, with baseline stage as the independent variable. RESULTS: Glaucoma surgery requirement was highly associated with baseline disease stage and IOP increase before surgery in the United States and somewhat associated with these factors in Europe. Within both locations, baseline IOP was highly associated with glaucoma surgery requirement. Controlling for covariates, patients at higher baseline stages incurred greater costs in the United States (P=0.0017) and Europe (P=0.0715). Surgery and medication were also highly predictive of increased cost (P<0.0001). Cost of care differed greatly between the European countries, with costs lowest in Italy. CONCLUSIONS: Increases in annual cost were related to higher baseline IOP, higher baseline stage, medication, and surgery. Thus, significant potential savings and reductions in annual healthcare burden are possible if patients are diagnosed and treated at earlier stages of glaucoma.

Bisphosphonate use in the treatment of Paget's disease of the bone: analysis of claims in a large database.

This study examines the use of bisphosphonates for treating Paget's disease of the bone through an analysis of drug, dose, and therapy-duration data. Data were obtained from a national, multi-managed care plan claims database (based on claims filed from 1996-2004). Patient eligibility criteria included at least one claim with Paget's disease International Classification of Diseases, Ninth Revision code 731.0, at least one bisphosphonate pharmacy claim, at least six months' continuous enrollment after initiating bisphosphonate therapy (index date), and no more than one claim for osteoporosis. The proportion of patients with bisphosphonate therapy extending beyond the initial recommended treatment regimen (incremental drug use) and associated costs were calculated for each drug. Of 433 patients with Paget's disease receiving bisphosphonate treatment (mean age, 65.0 yr; 64.3% women), 53.1% were prescribed alendronate at the index date; 34.9% and 7.4%, were prescribed risedronate and etidronate, respectively. More than 40% of patients with Paget's disease receiving at least one bisphosphonate were prescribed bisphosphonates beyond the recommended regimen duration at substantial incremental costs.

Chemotherapy and cardiotoxicity in older breast cancer patients: a population-based study.

PURPOSE: Adjuvant chemotherapy, especially with anthracyclines, is known to cause acute and chronic cardiotoxicity in breast cancer patients. We studied the cardiac effects of chemotherapy in a population-based sample of breast cancer patients aged > or = 65 years with long-term follow-up. PATIENTS AND METHODS: In the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we analyzed treatments and outcomes among women > or = 65 years of age who were diagnosed with stage I to III breast cancer from January 1, 1992 to December 31, 1999. Propensity scores were used to control for baseline heart disease (HD) and other known predictors of chemotherapy, and Cox proportional hazards models were used to estimate the risk of cardiomyopathy (CM), congestive heart failure (CHF), and HD after chemotherapy. RESULTS: Of 31,748 women with stage I to III breast cancer, 5,575 (18%) received chemotherapy. Chemotherapy was associated with younger age, fewer comorbidities, hormone receptor negativity, multiple primary tumors, and advanced disease. Patients who received chemotherapy were less likely than other patients to have pre-existing HD (45% v 55%, respectively; P < .001). The hazard ratios for CM, CHF, and HD for patients treated with doxorubicin (DOX) compared with patients who received no chemotherapy were 2.48 (95% CI, 2.10 to 2.93), 1.38 (95% CI, 1.25 to 1.52), and 1.35 (95% CI, 1.26 to 1.44), respectively. The relative risk of cardiotoxicity among patients who received DOX compared with untreated patients remained elevated 5 years after diagnosis. CONCLUSION: When baseline HD was taken into account, chemotherapy, especially with anthracyclines, was associated with a substantially increased risk of CM. As the number of long-term survivors grows, identifying and minimizing the late effects of treatment will become increasingly important.