Lucy Thuita

Unexpected Abrupt Increase in Left Ventricular Assist Device Thrombosis

BACKGROUND We observed an apparent increase in the rate of device thrombosis among patients who received the HeartMate II left ventricular assist device, as compared with preapproval clinical-trial results and initial experience. We investigated the occurrence of pump thrombosis and elevated lactate dehydrogenase (LDH) levels, LDH levels presaging thrombosis (and associated hemolysis), and outcomes of different management strategies in a multi-institutional study. METHODS We obtained data from 837 patients at three institutions, where 895 devices were implanted from 2004 through mid-2013; the mean (±SD) age of the patients was 55±14 years. The primary end point was confirmed pump thrombosis. Secondary end points were confirmed and suspected thrombosis, longitudinal LDH levels, and outcomes after pump thrombosis. RESULTS A total of 72 pump thromboses were confirmed in 66 patients; an additional 36 thromboses in unique devices were suspected. Starting in approximately March 2011, the occurrence of confirmed pump thrombosis at 3 months after implantation increased from 2.2% (95% confidence interval [CI], 1.5 to 3.4) to 8.4% (95% CI, 5.0 to 13.9) by January 1, 2013. Before March 1, 2011, the median time from implantation to thrombosis was 18.6 months (95% CI, 0.5 to 52.7), and from March 2011 onward, it was 2.7 months (95% CI, 0.0 to 18.6). The occurrence of elevated LDH levels within 3 months after implantation mirrored that of thrombosis. Thrombosis was presaged by LDH levels that more than doubled, from 540 IU per liter to 1490 IU per liter, within the weeks before diagnosis. Thrombosis was managed by heart transplantation in 11 patients (1 patient died 31 days after transplantation) and by pump replacement in 21, with mortality equivalent to that among patients without thrombosis; among 40 thromboses in 40 patients who did not undergo transplantation or pump replacement, actuarial mortality was 48.2% (95% CI, 31.6 to 65.2) in the ensuing 6 months after pump thrombosis. CONCLUSIONS The rate of pump thrombosis related to the use of the HeartMate II has been increasing at our centers and is associated with substantial morbidity and mortality.

Berlin Heart EXCOR Pediatric Ventricular Assist Device for Bridge to Heart Transplantation in US Children

Background— Recent data suggest that the Berlin Heart EXCOR Pediatric ventricular assist device is superior to extracorporeal membrane oxygenation for bridge to heart transplantation. Published data are limited to 1 in 4 children who received the device as part of the US clinical trial. We analyzed outcomes for all US children who received the EXCOR to characterize device outcomes in an unselected cohort and to identify risk factors for mortality to facilitate patient selection. Methods and Results— This multicenter, prospective cohort study involved all children implanted with the Berlin Heart EXCOR Pediatric ventricular assist device at 47 centers from May 2007 through December 2010. Multiphase nonproportional hazards modeling was used to identify risk factors for early (<2 months) and late mortality. Of 204 children supported with the EXCOR, the median duration of support was 40 days (range, 1–435 days). Survival at 12 months was 75%, including 64% who reached transplantation, 6% who recovered, and 5% who were alive on the device. Multivariable analysis identified lower weight, biventricular assist device support, and elevated bilirubin as risk factors for early mortality and bilirubin extremes and renal dysfunction as risk factors for late mortality. Neurological dysfunction occurred in 29% and was the leading cause of death. Conclusions— Use of the Berlin Heart EXCOR has risen dramatically over the past decade. The EXCOR has emerged as a new treatment standard in the United States for pediatric bridge to transplantation. Three-quarters of children survived to transplantation or recovery; an important fraction experienced neurological dysfunction. Smaller patient size, renal dysfunction, hepatic dysfunction, and biventricular assist device use were associated with mortality, whereas extracorporeal membrane oxygenation before implantation and congenital heart disease were not.

Should lung transplantation be performed for patients on mechanical respiratory support? The US experience

OBJECTIVE The study objectives were to (1) compare survival after lung transplantation in patients requiring pretransplant mechanical ventilation or extracorporeal membrane oxygenation with that of patients not requiring mechanical support and (2) identify risk factors for mortality. METHODS Data were obtained from the United Network for Organ Sharing for lung transplantation from October 1987 to January 2008. A total of 15,934 primary transplants were performed: 586 in patients on mechanical ventilation and 51 in patients on extracorporeal membrane oxygenation. Differences between nonsupport patients and those on mechanical ventilation or extracorporeal membrane oxygenation support were expressed as 2 propensity scores for use in comparing risk-adjusted survival. RESULTS Unadjusted survival at 1, 6, 12, and 24 months was 83%, 67%, 62%, and 57% for mechanical ventilation, respectively; 72%, 53%, 50%, and 45% for extracorporeal membrane oxygenation, respectively; and 93%, 85%, 79%, and 70% for unsupported patients, respectively (P < .0001). Recipients on mechanical ventilation were younger, had lower forced vital capacity, and had diagnoses other than emphysema. Recipients on extracorporeal membrane oxygenation were also younger, had higher body mass index, and had diagnoses other than cystic fibrosis/bronchiectasis. Once these variables, transplant year, and propensity for mechanical support were accounted for, survival remained worse after lung transplantation for patients on mechanical ventilation and extracorporeal membrane oxygenation. CONCLUSION Although survival after lung transplantation is markedly worse when preoperative mechanical support is necessary, it is not dismal. Thus, additional risk factors for mortality should be considered when selecting patients for lung transplantation to maximize survival. Reduced survival for this high-risk population raises the important issue of balancing maximal individual patient survival against benefit to the maximum number of patients.

Should lung transplantation be performed using donation after cardiac death? The United States experience

OBJECTIVE We compared 1) survival after lung transplantation of recipients of donation after cardiac death (DCD) versus brain death donor organs in the United States and 2) recipient characteristics. METHODS Data were obtained from the United Network for Organ Sharing for lung transplantation from October 1987 to May 2007. Follow-up after DCD lung transplantation extended to 8.6 years, median 1 year. Differences among recipients of DCD versus brain death donor organs were expressed as a propensity score for use in comparing risk-adjusted survival. RESULTS A total of 14,939 transplants were performed, 36 with DCD organs (9 single, 27 double). Among the 36 patients, 3 have died after 1 day, 11 days, and 1.5 years. Unadjusted survival at 1, 6, 12, and 24 months was 94%, 94%, 94%, and 87%, respectively, for DCD donors versus 92%, 84%, 78%, and 69%, respectively, for brain death donors (P = .04). DCD recipients were more likely to undergo double lung transplantation and have diabetes, lower forced 1-second expiratory volume, and longer cold ischemic times. Once these were accounted for and propensity adjusted, survival was still better for DCD recipients, although the P value equals .06. CONCLUSION Concern about organ quality and ischemia-reperfusion injury has limited the application of lung DCD. However, DCD as practiced in the United States results in survival at least equivalent to that after brain death donation. It also demonstrates selection bias, particularly in performing double lung transplantation, making generalization regarding survival difficult. Nevertheless, the data support the expanded use of DCD.

Meat and dairy consumption and subsequent risk of prostate cancer in a US cohort study

ObjectiveTo evaluate the association of meat and dairy food consumption with subsequent risk of prostate cancer.MethodsIn 1989, 3,892 men 35+ years old, who participated in the CLUE II study of Washington County, MD, completed an abbreviated Block food frequency questionnaire. Intake of meat and dairy foods was calculated using consumption frequency and portion size. Incident prostate cancer cases (n = 199) were ascertained through October 2004. Cox proportional hazards regression was used to calculate hazard ratios (HR) of total and advanced (SEER stages three and four; n = 54) prostate cancer and 95% confidence intervals (CI) adjusted for age, BMI at age 21, and intake of energy, saturated fat, and tomato products.ResultsIntakes of total meat (HR = 0.90, 95% CI 0.60–1.33, comparing highest to lowest tertile) and red meat (HR = 0.87, 95% CI 0.59–1.32) were not statistically significantly associated with prostate cancer. However, processed meat consumption was associated with a non-statistically significant higher risk of total (5+ vs. ≤1 servings/week: HR = 1.53, 95% CI 0.98–2.39) and advanced (HR = 2.24; 95% CI 0.90–5.59) prostate cancer. There was no association across tertiles of dairy or calcium with total prostate cancer, although compared to ≤1 serving/week consumption of 5+ servings/week of dairy foods was associated with an increased risk of prostate cancer (HR = 1.65, 95% CI 1.02–2.66).ConclusionOverall, consumption of processed meat, but not total meat or red meat, was associated with a possible increased risk of total prostate cancer in this prospective study. Higher intake of dairy foods but not calcium was positively associated with prostate cancer. Further investigation into the mechanisms by which processed meat and dairy consumption might increase the risk of prostate cancer is suggested.

Guidelines for Donor Lung Selection: Time for Revision?

BACKGROUND Few data support current guidelines for donor selection in lung transplantation. We determined degree of compliance with current donor guidelines, effect of these and variances on survival, and other donor factors predicting survival. METHODS From July 1999 to June 2008, 10,333 primary transplants were performed in the US, with United Network for Organ Sharing data available for age, ABO type, chest radiograph, arterial difference in partial pressure of oxygen (PaO(2)) greater than 300 on 100% fraction of inspired oxygen, smoking, absence of aspiration/sepsis, and purulent secretions. Multivariable survival methods were used to determine relevance of these and new variables, adjusted for recipient risk factors. RESULTS In 56% of transplants, variance from at least one guideline was observed: chest radiograph, 41%; smoking, 21%; and PaO(2), 18%; but rarely ABO compatibility (0.06%). Practice within guidelines was not associated with increased mortality. Common variances from guidelines; eg, PaO(2)/fraction of inspired oxygen down to 230, were not associated with increased mortality, but smoking (p = 0.02) was. New donor variables associated with increased mortality were diabetes (p = 0.001), presence of cytomegalovirus antibodies (p < 0.0001), recent smoking history (p = 0.02), African-American (p = 0.005), blood type A (p = 0.02), death other than from head trauma (p = 0.02), and gender (p = 0.02), race (p = 0.03), and size (p = 0.002) discordances. CONCLUSIONS Variance from current donor guidelines for lung transplantation is frequent; analysis suggests that donor PaO(2) ranges can be widened and a suspicious chest radiograph, evidence of sepsis, and purulent bronchial secretions ignored. Older age and smoking history appear to have a minor impact. New and possibly important factors identified suggest the need to better understand the impact of a wider range of donor variables on recipient outcomes.

Genetic variation in the nucleotide excision repair pathway and colorectal cancer risk.

Nucleotide excision repair (NER) enzymes are critical for the removal of bulky DNA adducts caused by environmental carcinogens, such as heterocyclic amines and polycyclic aromatic hydrocarbons, which are found in two putative risk factors for colorectal cancer, tobacco smoke and meat cooked at high temperature. To examine the association between common genetic variants in NER genes and the risk of colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Twenty-two single nucleotide polymorphisms in 11 NER genes were genotyped in 250 colorectal cancer cases and a subcohort of 2,224 participants. Incidence rate ratios (RR) and 95% confidence intervals (95% CI) were estimated using a modified Cox regression model and robust variance estimate. The ERCC6 1213G variant, which is thought to reduce NER capacity, was associated with an increased risk of colorectal cancer compared with the homozygous wild type (RR, 1.36; 95% CI, 1.00-1.86 and RR, 2.64; 95% CI, 1.53-4.58 for the RG and GG genotypes respectively with Ptrend = 0.0006). Having at least one XPC 492H allele was also associated with an increased risk of colorectal cancer (RR, 1.75; 95% CI, 1.20-2.57). When the combined effects of ERCC6 R1213G and XPC R492H were examined, the risk of colorectal cancer significantly increased with increasing number of variant alleles (Ptrend = 0.00003). Our study suggests that genetic polymorphisms in the NER genes, ERCC6 and XPC, may be associated with an increased risk of colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2263–9)

Mismatch repair polymorphisms and the risk of colorectal cancer

Rare germline variants in mismatch repair genes have been linked to hereditary nonpolyposis colorectal cancer; however, it is unknown whether common polymorphisms in these genes alter the risk of colorectal cancer. To examine the association between common variants in mismatch repair genes and colorectal cancer, we conducted a case‐cohort study within the CLUE II cohort. Four single nucleotide polymorphisms in 3 mismatch repair genes (MSH3 R940Q, MSH3 T1036A, MSH6 G39E and MLH1 I219V) were genotyped in 237 colorectal cancer cases and a subcohort of 2,189 participants. Incidence rate ratios (RRs) and 95% confidence intervals (95% CIs) for each polymorphism were estimated. The MSH3 1036A variant was found to be associated with an increased risk of colorectal cancer (RR = 1.28, 95% CI: 0.94–1.74 and RR = 1.65, 95% CI: 1.01–2.70 for the AT and TT genotypes, respectively, with ptrend = 0.02), particularly proximal colon cancer. Although the MSH3 940Q variant was only weakly associated with colorectal cancer overall (ptrend = 0.07), it was associated with a significant increased risk of proximal colon cancer (RR = 1.69, 95% CI: 1.10–2.61 and RR = 2.68, 95% CI: 0.96–7.47 for the RQ and QQ genotypes, respectively with ptrend = 0.005). Processed meat intake appeared to modify the association between the MSH3 polymorphisms and colorectal cancer (pinteraction < 0.10 for both). No association was observed with the MSH6 and MLH1 polymorphisms overall. This study suggests that common polymorphisms in the mismatch repair gene, MSH3, may increase the risk of colorectal cancer, especially proximal colon cancer.

Polymorphisms of the DNA repair genes XPD (Lys751Gln) and XRCC1 (Arg399Gln and Arg194Trp): relationship to breast cancer risk and familial predisposition to breast cancer

SummaryFamily history is a risk factor for breast cancer and could be due to shared environmental factors or polymorphisms of cancer susceptibility genes. Deficient function of DNA repair enzymes may partially explain familial risk as polymorphisms of DNA repair genes have been associated, although inconsistently, with breast cancer. This population based case–control study examined the association between polymorphisms in XPD (Lys751Gln) and XRCC1 (Arg399Gln and Arg194Trp) genes, and breast cancer. Breast cancer cases (n=321) and controls (n=321) were matched on age and menopausal status. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). The analysis was conducted omitting observations with missing data, and by using imputation methods to handle missing data. No significant association was observed between the XPD 751Gln/Lys (OR 1.37, 95% CI 0.96–1.96) and Gln/Gln genotypes (OR 1.08, 95% CI 0.62–1.86) (referent Lys/Lys), XRCC1 399Arg/Gln (OR 1.48, 95% CI 0.92–2.38) and Gln/Gln genotypes (1.11, 95% CI 0.67–1.83) (referent Arg/Arg) or the XRCC1 Arg/Trp and Trp/Trp genotypes (OR 1.12, 95% CI 0.69–1.83) (referent Arg/Arg) and breast cancer. In multivariate analysis, the adjusted odds ratios for the XPD and XRCC1 399 polymorphisms increased and became statistically significant, however, were attenuated when imputation methods were used to handle missing data. There was no interaction with family history. These results indicate that these polymorphisms in XPD and XRCC1 genes are only weakly associated with breast cancer. Without imputation methods for handling missing data, a statistically significant association was observed between the genotypes and breast cancer, illustrating the potential for bias in studies that inadequately handle missing data.

Major Bleeding During HeartMate II Support

OBJECTIVES The aim of this study was to characterize a single-center experience of major bleeding complications during HeartMate II (HMII) (Thoratec Corp., Pleasanton, California) left ventricular assist device support, with focus on the subtypes and temporal patterns of post-operative bleeding. BACKGROUND Bleeding complications are the most common post-operative adverse events after HMII implantation. The timing of bleeding events, relationship to coagulation status, and effect on post-operative survival are incompletely understood. METHODS From October 2004 to June 2010, 139 HMII recipients at the Cleveland Clinic received 145 devices as a bridge to transplant or destination therapy for advanced heart failure. Major bleeding was defined using Interagency Registry for Mechanically Assisted Circulatory Support criteria, with an additional category created to maximize sensitivity for events. Pre-operative variables, coagulation status, and bleeding recurrence were assessed for correlation to primary events using modulated renewal within a multivariable analysis. RESULTS The cumulative occurrence of major bleeding was 58% during 171 patient-years of follow-up. There were 1.14 major bleeds per patient-year, with 44% occurring as repeat bleeding events. A first bleed did not predict subsequent bleeding. The greatest risk of bleeding was noted within 2 weeks post-implantation. The international normalized ratio profile correlated poorly with the risk of bleeding. Bleeding early after surgery was associated with reduced survival while on HMII support. CONCLUSIONS The risk of bleeding peaks early after HMII implantation. Bleeding of thoracic and gastrointestinal sources dominates these events, although many patients undergo transfusions for anemia without an apparent source of hemolysis or bleeding.