Tabelecleucel for EBV+ PTLD following allogeneic HCT or SOT in a multicenter expanded access protocol.

Patients with Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disease (EBV+ PTLD) in whom initial treatment fails have few options and historically low median overall survival (OS) of 0.7 months following allogeneic hematopoietic cell transplant (HCT) and 4.1 months following solid organ transplant (SOT). Tabelecleucel is an off-the-shelf, allogeneic EBV-specific cytotoxic T-lymphocyte immunotherapy for EBV+ PTLD. Previous single-center experience showed responses in patients with EBV+ PTLD following HCT or SOT. We now report outcomes from a multicenter expanded access protocol (NCT02822495) in HCT (n = 14) and SOT (n = 12) recipients treated with tabelecleucel for EBV+ PTLD that was relapsed/refractory to rituximab ± chemotherapy. The investigator-assessed objective response rate was 65.4% overall (including 38.5% with a complete and 26.9% with a partial response), 50.0% in HCT, and 83.3% in SOT. The estimated 1- and 2-year OS rates (95% CI) were both 70.0% (46.5, 84.7) overall, both 61.5% (30.8, 81.8) in HCT, and both 81.5% (43.5, 95.1) in SOT (median follow-up: 8.2, 2.8, and 22.5 months, respectively). Patients responding to tabelecleucel had higher 1- and 2-year OS rates (94.1%) than non-responders (0%). Treatment was well tolerated with no reports of tumor flare, cytokine release syndrome, or rejection of marrow and SOT. Results demonstrate clinically meaningful outcomes across a broad population treated with tabelecleucel, indicating a potentially transformative and accessible treatment advance for relapsed/refractory EBV+ PTLD following HCT or SOT.

Unidirectional alteration of methylation and hydroxymethylation at the promoters and differential gene expression in oral squamous cell carcinoma.

Background: Oral squamous cell carcinoma (OSCC) is one of the most common types of cancer worldwide. Although overall losses of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) have been previously observed, a genome-wide, single-base-resolution, and simultaneous mapping of 5mC and 5hmC in OSCC is still unaccomplished. Similarly, the mechanism of how 5mC and 5hmC collectively lead to abnormal gene expression in OSCC is largely unexplored. Using parallel whole-genome bisulfite sequencing (WGBS) and whole-genome oxidative bisulfite sequencing (oxWGBS), we characterized 5mC- and 5hmC-profiles at single-nucleotide resolution in paired primary OSCC samples and their normal adjacent tissues (NATs). We also analyzed the effect of 5mC- and 5hmC-modifications on differential gene expression in OSCC using multi-omics analysis. Results: An overall reduction of both 5mC and 5hmC in various genomic regions have been observed in OSCC samples. At promoter regions, a total of 6,921 differentially methylated regions and 1,024 differentially hydroxymethylated regions were identified in OSCC. Interestingly, compared to bidirectional modification with 5mC and 5hmC, unidirectional modification with 5mC and 5hmC at the promoters is associated with bigger change in the gene expression. Additionally, genes bearing unidirectional modification with 5mC and 5hmC at the promoters are enriched in signaling pathways like cell proliferation, cell differentiation, and receptor tyrosine kinase pathway that are essential for the tumorigenesis. Finally, the grouped expression signature of top 20 genes bearing promoter-unidirectional-modification with 5mC and 5hmC tends to correlate with the clinical outcome of certain subtypes of head and neck squamous cell carcinoma. Conclusion: Using parallel WGBS and oxWGBS analyses, we observed an overall reduction of 5mC- and 5hmC-modifications at various genomic regions in OSCC. Unidirectional modification with 5mC and 5hmC at the promoters is associated with enhanced changes in gene expression in OSCC tissues. Furthermore, such differentially expressed genes bearing unidirectional modifications with 5mC and 5hmC at the promoters might have clinical relevance to the outcome of OSCC.

Association between selected folate pathway polymorphisms and nonsyndromic limb reduction defects: a case-parental analysis.

Inadequate folate status resulting from either genetic variation or nutritional deficiencies has been associated with an increased risk of congenital malformations including orofacial clefting, limb, cardiac and neural tube defects. Few epidemiological studies have examined the association between limb reduction defects (LRDs) and folate-related genetic polymorphisms other than MTHFR 677C→T. We conducted a case-parental analysis of 148 families who participated in the National Birth Defects Prevention Study to examine the association between nonsyndromic transverse and longitudinal LRDs with five single nucleotide polymorphisms (SNPs) in genes encoding enzymes in folate and methionine pathways. Log-linear Poisson regression, adapted for analysis of case-parental data assuming an additive genetic model, was used to estimate genetic relative risks and 95% confidence intervals for the association between LRDs and each SNP. Among women who did not take multivitamin supplements, the MTHFR 677T variant acts via the offspring's genome to increase the risk of LRDs. No association between LRDs and any fetal SNP was found among women who used multivitamin supplements. These results suggest the possibility that initiating folic acid supplementation prior to pregnancy may reduce the risk of having a LRD-affected pregnancy, especially in women whose offspring inherit one or two copies of the MTHFR 677T variant.

Maternal DNA hypomethylation and congenital heart defects.

BACKGROUND: Congenital heart defects (CHDs) are among the most prevalent and serious of birth defects. Multiple maternal factors are thought to contribute to CHD development, including folate intake. Maternal DNA methylation, which is dependent on folate metabolism, may impact the risk of CHDs. Our study was designed to determine whether maternal long interspersed nucleotide elements-1 (LINE-1) DNA hypomethylation is associated with increased occurrence of non-syndromic CHDs and whether maternal folate-dependent metabolites are correlated with DNA methylation status. METHODS: Using a case-control study design, we measured global DNA methylation status among mothers whose pregnancies were affected by non-syndromic CHDs (n = 180) and mothers of unaffected pregnancies (n = 187). Methylation of LINE-1 was used as a surrogate marker of global DNA methylation status. The association between DNA methylation and CHD risk was determined while adjusting for selected lifestyle factors. RESULTS: LINE-1 DNA methylation was significantly lower in cases compared to controls (p = 0.049). After covariate adjustments, a significant difference between cases and controls remained (p = 0.010). Among women with LINE-1 methylation in the lowest decile of DNA methylation, the estimated risk of having a CHD-affected pregnancy was almost twice that of women in all other deciles (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.03-3.58). CONCLUSIONS: Our findings indicate that maternal LINE-1 DNA hypomethylation is associated with an increased risk of CHDs. Future studies investigating the association between maternal DNA methylation patterns and CHDs should be pursued.

Incidence and risk factors for lower alimentary tract mucositis after 1529 courses of chemotherapy in a homogenous population of oncology patients: clinical and research implications.

BACKGROUND: Lower alimentary tract mucositis is a serious complication of chemotherapy. The aim of the study was to determine the incidence, risk factors, and mortality of lower alimentary tract mucositis in a homogeneous population of patients with newly diagnosed myeloma receiving similar antineoplastic therapy and standardized supportive care. METHODS: Lower alimentary tract mucositis was evaluated among 303 consecutive patients with myeloma (2004-2007) enrolled in a clinical trial consisting of induction chemotherapy, tandem melphalan-based autologous stem cell transplantation (ASCT), and consolidation. Lower alimentary tract mucositis was defined as neutropenia-associated grade II-IV enteritis/colitis. Pretreatment risk factors were examined including body surface area (BSA), serum albumin (albumin), and estimated creatinine clearance (CrCl). Multiple logistic regression model was used to compute adjusted odds ratio (OR) and 95% confidence intervals (CI). RESULTS: Forty-seven (15.5%) patients developed lower alimentary tract mucositis during 1529 courses of chemotherapy (including 536 melphalan-based ASCT). Pre-enrollment BSA <2 m² (OR, 2.768; 95% CI, 1.200-6.381; P = .0169) increased the risk for lower alimentary tract mucositis, whereas higher albumin was protective (OR, 0.698; 95% CI, 0.519-0.940; P = .0177). Pretransplant variables associated with lower alimentary tract mucositis were BSA <2 m² (OR, 4.451; 95% CI, 1.459-13.58, P = .0087) and estimated CrCl <60 mL/min (OR, 3.493; 95% CI, 1.173-10.40; P = .0246). Higher albumin level conferred protection (OR, 0.500; 95% CI, 0.304-0.820; P = .0061). No lower alimentary tract mucositis-related death was observed. CONCLUSIONS: Lower alimentary tract mucositis is not uncommon among a homogenous population of oncology patients undergoing sequential courses of chemotherapy including melphalan-based ASCT but does not contribute to mortality. Lower BSA, renal function, and albumin are associated with increased risk for lower alimentary tract mucositis.

Maternal folate-related gene environment interactions and congenital heart defects.

OBJECTIVE: To investigate whether women with congenital heart defect (CHD)-affected pregnancies were more likely to have functional single-nucleotide polymorphisms in genes encoding enzymes in folate-dependent pathways. METHODS: A population-based case-control study of 572 women with CHD-affected pregnancies and 363 women in the control group was conducted. DNA samples were genotyped for single-nucleotide polymorphisms in three genes encoding for folate pathway enzymes. Maternal lifestyle factor information was obtained using standardized interviews. RESULTS: Women in the case group were 1.5 times more likely to be obese (body mass index of 30 or higher) compared with those in the control group. Obese women carrying the MTHFR TT genotype were 4.6 times more likely to have an affected pregnancy compared with normal-weight women carrying a CC genotype. Obese women carrying one or two copies of the A allele in the BHMT polymorphism were 1.8 times more likely to have a CHD-affected pregnancy than were normal-weight women carrying a BHMT GG genotype. Among women who smoked, those carrying a TCII CG or GG genotype were 1.8 times more likely to have an affected fetus than were women who smoked and carried a CC genotype. Among women who drank alcohol, those carrying a TCII CG or GG genotype were 1.7 times more likely to have an affected fetus than were women who drank and carried a CC genotype. CONCLUSION: Results indicate that functional polymorphisms in folate-related genes increase the risk of having a fetus with CHD when maternal lifestyle factors that alter folate metabolism are present. LEVEL OF EVIDENCE: II.

Cluster analysis of women's prodromal and acute myocardial infarction symptoms by race and other characteristics.

BACKGROUND AND OBJECTIVE: Although research has identified women's prodromal and acute myocardial infarction (MI) symptoms, diagnosing coronary heart disease in women remains challenging. Knowing how individual symptoms cluster by race and other characteristics would provide key diagnostic information. We performed a secondary analysis to: (a) generate naturally occurring symptom clusters based on prodromal and acute MI symptom scores separately, (b) examine the association between women's characteristics and symptom clusters, and (c) describe the percentage of women who reported experiencing the same symptoms in both prodromal and acute MI phases. SUBJECT AND METHODS: The database contained retrospective self-reported data obtained by telephone survey from 1270 women (43% black, 42% white, 15% Hispanic) with a confirmed MI recruited from 15 geographically diverse sites. Data included frequency and severity of 33 prodromal symptoms, intensity of 37 acute MI symptoms, and comorbidities/risk factors. We used both bivariate and multivariate analyses to examine associations between cluster assignment and characteristics/risk factors. Because of the possibility of complex interactions, we explored nonlinear interactions with recursive partitioning. RESULTS: Cluster analysis yielded 3 naturally occurring clusters for each of the prodromal and acute symptom sets. Each cluster contained women who reported increasing frequency and severity of symptoms. Six characteristics (age, race, body mass index, personal history of heart disease, diabetes, smoking status) were strongly associated with the clusters. Body mass index was the most important factor in classifying prodromal symptoms, whereas age was for acute symptoms. CONCLUSIONS: Black women younger than 50 years were more likely to report frequent and intense prodromal symptoms, whereas older white women reported the least. Younger, obese, diabetic black women reported the most acute symptoms, whereas older nonobese, nondiabetic white women reported the fewest. Symptom clusters and characteristics of women in these clusters provide valuable diagnostic information. Further research with a control group is needed.

Racial differences in women's prodromal and acute symptoms of myocardial infarction.

BACKGROUND: Minority women, especially black and Hispanic women, have higher rates of coronary heart disease and resulting disability and death than do white women. A lack of knowledge of minority women's symptoms of coronary heart disease may contribute to these disparities. OBJECTIVE: To compare black, Hispanic, and white women's prodromal and acute symptoms of myocardial infarction. METHODS: In total, 545 black, 539 white, and 186 Hispanic women without cognitive impairment at 15 sites were retrospectively surveyed by telephone after myocardial infarction. With general linear models and controls for cardiovascular risk factors, symptom severity and frequency were compared among racial groups. Logistic regression models were used to examine individual prodromal or acute symptoms by race, with adjustments for cardiovascular risk factors. RESULTS: Among the women, 96% reported prodromal symptoms. Unusual fatigue (73%) and sleep disturbance (50%) were the most frequent. Eighteen symptoms differed significantly by race (P<.01); blacks reported higher frequencies of 10 symptoms than did Hispanics or whites. Thirty-six percent reported prodromal chest discomfort; Hispanics reported more pain/discomfort symptoms than did black or white women. Minority women reported more acute symptoms (P < .01). The most frequent symptom, regardless of race, was shortness of breath (63%); 22 symptoms differed by race (P <.01). In total, 28% of Hispanic, 38% of black, and 42% of white women reported no chest pain/discomfort. CONCLUSIONS: Prodromal and acute symptoms of myocardial infarction differed significantly according to race. Racial descriptions of women's prodromal and acute symptoms should assist providers in interpreting women's symptoms.

Strong correlation between serum aspergillus galactomannan index and outcome of aspergillosis in patients with hematological cancer: clinical and research implications.

BACKGROUND: Galactomannan is an Aspergillus-specific polysaccharide released during aspergillosis and is detected by the quantitative serum galactomannan index (GMI) test. Preclinical and preliminary clinical reports have suggested a good correlation between GMI and aspergillosis outcome. METHODS: We reviewed the literature to assess the strength of correlation between GMI and aspergillosis outcome using the kappa correlation coefficient. We included 27 studies that enrolled patients with hematological cancer and proven or probable aspergillosis and that used sequential GMI testing. We examined the 3 following outcomes: survival (survival vs. death), global outcome (survival vs. death [including autopsy findings]), and autopsy outcome (autopsy findings only). RESULTS: Overall, 257 patients fulfilled criteria for proven or probable aspergillosis and were eligible for outcome evaluation. Correlation between GMI (within

Serum Aspergillus galactomannan antigen values strongly correlate with outcome of invasive aspergillosis: a study of 56 patients with hematologic cancer.

BACKGROUND: Determining the outcome of patients with aspergillosis can be particularly difficult because patients with aspergillosis are at risk for other conditions that mimic this infection. Galactomannan is an Aspergillus-specific antigen released during invasive aspergillosis and is detected by the quantitative serum galactomannan index (GMI) test. METHODS: Using a kappa correlation coefficient test (KCC), the strength of correlation was determined between GMI and survival outcome of aspergillosis among 56 adults with hematologic cancer (90% had myeloma) who underwent serial GMI monitoring until hospital discharge or death. RESULTS: All 56 patients received antineoplastic therapy (myeloablative followed by stem cell transplantation [autologous in 21 patients and allogeneic in 3 patients] or nonmyeloablative therapy [32 patients]). The overall correlation between survival outcome and GMI was excellent (KCC = 0.8609; 95% confidence interval [95% CI], 0.7093-1.000 [P < .0001]) and was comparable among neutropenic and nonneutropenic patients (KCC = 0.8271; 95% CI, 0.6407-1.000 [P < .0001] and KCC = 1.0; 95% CI, 1-1 [P = .0083], respectively). CONCLUSIONS: The survival outcome of patients with aspergillosis strongly correlated with serum GMI. These findings have important implications for patient care and clinical trials of mold-active antifungal agents.

Association between congenital heart defects and small for gestational age.

OBJECTIVES: Infants with congenital heart defects may experience inhibited growth during fetal life. In a large case-control study, we addressed the hypothesis that infants with congenital heart defects are more likely to be small for gestational age than infants without congenital heart defects after controlling for selected maternal and infant characteristics. METHODS: Using data from population-based birth defect registries, the National Birth Defects Prevention Study enrolled infants with nonsyndromic congenital heart defects (case subjects) and infants without congenital heart defects or any other birth defect (control subjects). Small for gestational age was defined as birth weight below the 10th percentile for gestational age and gender. Association between congenital heart defects and small for gestational age was examined by conditional logistic regression adjusting for maternal covariates related to fetal growth. RESULTS: Live-born singleton infants with congenital heart defects (case subjects, n = 3395) and live-born singleton infants with no birth defect (control subjects, n = 3924) were included in this study. Case subjects had lower birth weights compared with control subjects. Small for gestational age was observed among 15.2% of case subjects and among only 7.8% of control subjects. Congenital heart defect infants were significantly more likely to be small for gestational age than control infants. CONCLUSIONS: Infants with congenital heart defects are approximately twice as likely to be small for gestational age as control subjects. Small for gestational age status may affect clinical management decisions, therapeutic response, and prognosis of neonates with congenital heart defects. Although the etiology of growth retardation among infants with congenital heart defects is uncertain, further exploration may uncover a common pathogenesis or causal relationship between congenital heart defects and small for gestational age.

[Apoptosis in myocardial cells after macleaya cordata total alkaloids poisoning in rats].

OBJECTIVE: To observe pathological changes and apoptosis in rats myocardial cells after Macleaya cordata total alkaloids poisoning, and to provide some references for Macleaya cordata total alkaloids poisoning detection. METHODS: An experimental model of Macleaya cordata total alkaloids poisoning was established, and the technology of TUNEL staining was used.The results were analyzed by computer image analysis competitive system. RESULTS: Quantities of apoptosis in myocardial cells in poisoning groups were much more than those in the control groups at different tages (P<0.01). In addition the quantities of apoptosis were different after different poisoning duration. CONCLUSION: Although clinical symptoms was not obvious and could not be detected by poison analysis. Pathological changes induced by Macleaya cordata total alkaloids could be found through the apoptosis detection.

Neural tube defects and maternal biomarkers of folate, homocysteine, and glutathione metabolism.

BACKGROUND: Alterations in maternal folate and homocysteine metabolism are associated with neural tube defects (NTDs). The role played by specific micronutrients and metabolites in the causal pathway leading to NTDs is not fully understood. METHODS: We conducted a case-control study to investigate the association between NTDs and maternal alterations in plasma micronutrients and metabolites in two metabolic pathways: methionine remethylation and glutathione transsulfuration. Biomarkers were measured in a population-based sample of women who had NTD-affected pregnancies (n = 43) and a control group of women who had a pregnancy unaffected by a birth defect (n = 160). We compared plasma concentrations of folate, vitamin B(12), vitamin B(6), methionine, S-adenosylmethionine (SAM), s-adenosylhomocysteine (SAH), adenosine, homocysteine, cysteine, and reduced and oxidized glutathione between cases and controls after adjusting for lifestyle and sociodemographic factors. RESULTS: Women with NTD-affected pregnancies had significantly higher plasma concentrations of SAH (29.12 vs. 23.13 nmol/liter, P = .0011), adenosine (0.323 vs. 0.255 mumol/liter; P = .0269), homocysteine (9.40 vs. 7.56 micromol/liter; P < .001), and oxidized glutathione (0.379 vs. 0.262 micromol/liter; P = .0001), but lower plasma SAM concentrations (78.99 vs. 83.16 nmol/liter; P = .0172) than controls. This metabolic profile is consistent with reduced methylation capacity and increased oxidative stress in women with affected pregnancies. CONCLUSIONS: Increased maternal oxidative stress and decreased methylation capacity may contribute to the occurrence of NTDs. Further analysis of relevant genetic and environmental factors is required to define the basis for these observed alterations.

Congenital heart defects and maternal biomarkers of oxidative stress.

BACKGROUND: Women who have had pregnancies that were affected by nonsyndromic congenital heart defects have alterations in the homocysteine-methionine pathway that may indicate increased exposure to oxidative stress or reduced antioxidant defense or both. OBJECTIVE: Our goal was to establish a maternal metabolic risk profile for nonsyndromic congenital heart defects that would enhance current preventive strategies. DESIGN: Using a case-control design, we measured biomarkers of the transsulfuration pathway in a population-based sample of women whose pregnancies were affected by congenital heart defects (331 cases) and in a control group of women (125 controls). Plasma concentrations of reduced and oxidized glutathione, vitamin B-6, homocysteine, cysteine, cysteinylglycine (CysGly), and glutamylcysteine (GluCys) were compared between cases and controls after adjustment for lifestyle and sociodemographic variables. RESULTS: After covariate adjustment, cases had significantly lower mean plasma concentrations of reduced glutathione (P < 0.0001), GluCys (P < 0.0001), and vitamin B-6 (P = 0.0023) and significantly higher mean concentrations of homocysteine (P < 0.0001) and oxidized glutathione (P < 0.0001) than did controls. CONCLUSIONS: Biomarkers of oxidative stress involved in the transsulfuration pathway were significantly higher in women with pregnancies affected by congenital heart defects than in women without such a history. Further analysis of relevant biomarkers of oxidative stress and genetic and environmental factors is required to define the basis for the observed alterations. Identifying the nature and extent of alterations in biomarkers of oxidative stress may suggest primary intervention strategies and provide clues to a greater understanding of the pathogenesis of congenital heart defects.

Congenital heart defects and abnormal maternal biomarkers of methionine and homocysteine metabolism.

BACKGROUND: It is well established that folic acid prevents neural tube defects. Although the mechanisms remain unclear, multivitamins containing folic acid may also protect against other birth defects, including congenital heart defects. OBJECTIVE: Our goal was to establish a maternal metabolic risk profile for nonsyndromic congenital heart defects that would enhance current preventive strategies. DESIGN: Using a case-control design, we measured biomarkers of the folate-dependent methionine and homocysteine pathway among a population-based sample of women whose pregnancies were affected by congenital heart defects (224 case subjects) or unaffected by any birth defect (90 control subjects). Plasma concentrations of folic acid, homocysteine, methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), vitamin B-12, and adenosine were compared, with control for lifestyle and sociodemographic variables. RESULTS: After covariate adjustment, case subjects had higher mean concentrations of homocysteine (P < 0.001) and SAH (P < 0.001) and lower mean concentrations of methionine (P = 0.019) and SAM (P = 0.014) than did control subjects. Vitamin B-12, folic acid, and adenosine concentrations did not differ significantly between case and control subjects. Homocysteine, SAH, and methionine were identified as the most important biomarkers predictive of case or control status. CONCLUSIONS: The basis for the observed abnormal metabolic profile among women whose pregnancies were affected by congenital heart defects cannot be defined without further analysis of relevant genetic and environmental factors. Nevertheless, a metabolic profile that is predictive of congenital heart defect risk would help to refine current nutritional intervention strategies to reduce risk and may provide mechanistic clues for further experimental studies.

Maternal use of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), and muscular ventricular septal defects.

BACKGROUND: Muscular ventricular septal defects (mVSDs) are the most common congenital heart defects. Previous studies have suggested maternal use of acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), and/or fever as risk factors. We evaluated the association between mVSDs and maternal use of acetaminophen or NSAIDs adjusting for fever. METHODS: Infants with nonsyndromic mVSDs (cases) and without birth defects (controls), with gestational age > or =37 weeks and their mothers were enrolled in the National Birth Defects Prevention Study. Two exposure periods were defined: the first trimester of pregnancy, and one month before pregnancy through delivery. Mothers reporting fever or medication use at least once during either period were considered exposed. Adjusted odds ratios and 95% confidence intervals were estimated independently for each exposure period. RESULTS: The analysis included 168 cases and 692 controls. Two case groups were evaluated: all mVSD infants (n = 168) (including those with associated minor cardiac defects or noncardiac defects), and infants with isolated mVSDs (n = 133). Mothers of cases were less likely to be African-American than Caucasian (OR, 0.36; 95% CI, 0.18, 0.73). Approximately equal numbers of case mothers and control mothers (10.4 versus 9.7%, respectively) reported at least one febrile episode during the first trimester. Neither acetaminophen nor NSAID exposure was significantly associated with mVSDs. This was true for both case groups and both exposure periods. CONCLUSIONS: Significant associations were not detected between the occurrence of mVSDs and maternal use of NSAIDs or acetaminophen adjusting for maternal fever, nor were they detected between maternal fever and mVSDs.

First-year survival of infants born with congenital heart defects in Arkansas (1993-1998): a survival analysis using registry data.

BACKGROUND: In the United States and other developed nations, birth defects are the leading cause of infant mortality. Congenital heart defects (CHDs) are among the most prevalent and fatal of all birth defects. Here we report the survival probability of infants born with CHDs in Arkansas and examine the impact of multiple malformations on survival. METHODS: Birth and death certificate records were linked to birth defects registry data for infants born with CHDs from January 1993 through December 1998 in Arkansas. Both neonatal and first-year survival probabilities were estimated. These were computed non-parametrically using Kaplan-Meier's product limit method. A Cox proportional-hazards model was used to evaluate the relative importance of additional malformations on survival. RESULTS: A total of 1,983 infants with CHDs were included in this study. The neonatal survival probability for this cohort was 94.0% (95% CI: 93.0%, 95.1%), and the first-year survival probability was 88.2% (95% CI: 86.8%, 89.6%). The presence of hypoplastic left heart syndrome conferred the greatest reduction in survival, whereas infants with pulmonic valve stenosis and infants with ventricular septal defects had the highest first-year survival. Infants with multiple CHDs had decreased survival compared to those with isolated heart defects. Survival was also adversely affected by the presence of congenital abnormalities in other body systems. CONCLUSIONS: Neonatal and first-year survival of infants with CHDs varies by both the type of cardiac malformation and the presence of additional cardiac and non-cardiac malformations. Further work will focus on the effects of maternal and infant characteristics on survival.