Evaluation and Management of Patients With Heart Disease and Cancer: Cardio-Oncology

The care for patients with cancer has advanced greatly over the past decades. A combination of earlier cancer diagnosis and greater use of traditional and new systemic treatments has decreased cancer-related mortality. Effective cancer therapies, however, can result in short- and long-term comorbidities that can decrease the net clinical gain by affecting quality of life and survival. In particular, cardiovascular complications of cancer treatments can have a profound effect on the health of patients with cancer and are more common among those with recognized or unrecognized underlying cardiovascular diseases. A new discipline termed cardio-oncology has thus evolved to address the cardiovascular needs of patients with cancer and optimize their care in a multidisciplinary approach. This review provides a brief introduction and background on this emerging field and then focuses on its practical aspects including cardiovascular risk assessment and prevention before cancer treatment, cardiovascular surveillance and therapy during cancer treatment, and cardiovascular monitoring and management after cancer therapy. The content of this review is based on a literature search of PubMed between January 1, 1960, and February 1, 2014, using the search terms cancer, cardiomyopathy, cardiotoxicity, cardio-oncology, chemotherapy, heart failure, and radiation.     

Prostate Cancer Ki-67 (MIB-1) Expression,Perineural Invasion,and Gleason Score as Biopsy-Based Predictors of Prostate Cancer Mortality: The Mayo Model

ObjectiveTo determine the role of cellular proliferation and other biopsy-based features in the prediction of prostate cancer mortality.Patients and MethodsBetween 1993 and 2012, our institution has performed quantitation of prostate cancer DNA ploidy and Ki-67 (MIB-1) on most prostate cancer needle biopsy specimens. The outcomes of 451 consecutive patients with biopsy-proven cancer treated by radical prostatectomy between January 24, 1995, and December 29, 1998, without neoadjuvant hormonal therapy were assessed. Clinical and biopsy information obtained before radical prostatectomy was placed in multivariate Cox proportional hazards regression models to predict local or systemic progression and cancer-specific death. Predictive ability was evaluated using a concordance index.ResultsWith a median follow-up of 12.9 years, 46 patients experienced local or systemic progression, and 18 patients died of prostate cancer. On multivariate analysis, the biopsy features of Ki-67 expression, perineural invasion, and Gleason score were associated with local or systemic progression. Ki-67 expression, perineural invasion, and Gleason score were associated with cancer-specific death with a concordance index of 0.892. After adjusting for perineural invasion and Gleason score, each 1% increase in Ki-67 expression was associated with a 12% increased risk of cancer-specific death (P<.001). Ki-67 expression alone was a strong predictor of cancer-specific outcomes and improved the predictive ability of currently used algorithms.ConclusionThis study documents that long-term prostate cancer outcomes are best estimated with a combination of Gleason score, perineural invasion, and Ki-67 expression. Given its low cost, rapid assessment, and strong predictive power, we believe that adding Ki-67 expression to perineural invasion and Gleason score at biopsy should be considered a standard by which all new biomarkers are compared before introducing them into clinical practice.     

Comparative Effectiveness of Telaprevir-Based Triple Therapy in Patients With Chronic Hepatitis C

ObjectiveTo examine the effectiveness and tolerability of triple therapy with pegylated interferon (p-IFN), ribavirin (RBV), and telaprevir in patients with chronic hepatitis C receiving treatment in an academic practice setting and in a more clinically diverse population compared with patients receiving treatment in phase 3 trials.Patients and MethodsA prospective database of all patients with viral hepatitis undergoing antiviral therapy from January 1, 2006, to July 1, 2012, was queried to identify treatment-naive and -experienced patients with chronic hepatitis C receiving dual and triple therapies. On-treatment response categories included rapid virologic response, extended rapid virologic response, early virologic response, and sustained virologic response. These patients were compared with matched controls, namely, patients who underwent dual therapy with p-IFN and RBV. Matching was performed for age, cirrhosis status, and prior treatment.ResultsThere were 55 patients who received triple therapy and met the eligibility criteria, consisting of treatment-naive (n=35) and -experienced patients (n=20: those with relapse, 9; those with nonresponse, 9; and those who terminated the treatment early, 2). Rapid virologic response was achieved in 41% of the patients, extended rapid virologic response in 41%, and early virologic response in 75%. Sustained virologic response was observed in 51% (18/35) of treatment-naive patients, 67% (6/9) of the patients with prior nonresponse, and 56% (5/9) of those with prior relapse. Corresponding results after dual therapy were 37% (23/62), 11% (2/18), and 27% (3/11), respectively. The mean decrease in the hemoglobin level at weeks 4, 8, and 24 of triple therapy was 2.8, 3.8, and 3.2 mg/dL compared with 2.4, 2.6, and 2.4 mg/dL with dual therapy (to convert mg/dL to mmol/L, multiply values by 0.0259).ConclusionTelaprevir-based triple therapy in clinical practice is considerably more effective than dual therapy with p-IFN and RBV despite the significant degree of anemia that complicated therapy, requiring RBV dose reduction and erythropoietin support.     

Myocardial Infarction Risk Among Patients With Fractures Receiving Bisphosphonates

ObjectiveTo determine if bisphosphonates are associated with reduced risk of acute myocardial infarction (AMI).Patients and MethodsA cohort of 14,256 veterans 65 years or older with femoral or vertebral fractures was selected from national administrative databases operated by the US Department of Veterans Affairs and was derived from encounters at Veterans Affairs facilities between October 1, 1998, and September 30, 2006. The time to first AMI was assessed in relationship to bisphosphonate exposure as determined by records from the Pharmacy Benefits Management Database. Time to event analysis was performed using multivariate Cox proportional hazards regression. An adjusted survival analysis curve and a Kaplan-Meier survival curve were analyzed.ResultsAfter controlling for atherosclerotic cardiovascular disease risk factors and medications, bisphosphonate use was associated with an increased risk of incident AMI (hazard ratio, 1.38; 95% CI, 1.08-1.77; P=.01). The timing of AMI correlated closely with the timing of bisphosphonate therapy initiation.ConclusionOur observations in this study conflict with our hypothesis that bisphosphonates have antiatherogenic effects. These findings may alter the risk-benefit ratio of bisphosphonate use for treatment of osteoporosis, especially in elderly men. However, further analysis and confirmation of these findings by prospective clinical trials is required.     

Treatment Discontinuations With New Oral Agents for Long-term Anticoagulation: Insights From a Meta-analysis of 18 Randomized Trials Including 101,801 Patients

ObjectiveTo systematically examine discontinuation rates with new US Food and Drug Administration–approved oral anticoagulants (NOACs) in patients with various indications for long-term anticoagulation.Patients and MethodsPoor adherence to medications is considered a potential and frequent cause of treatment failure. We searched the PubMed, Cochrane Central Register of Controlled Trials, EMBASE, EBSCO, Web of Science, and CINAHL databases for articles published from January 1, 2001, through September 15, 2013. The following Medical Subject Heading terms and/or keywords were used for our database searches: rivaroxaban, dabigatran, apixaban, new oral anticoagulants, oral thrombin inhibitors, and oral factor Xa inhibitors. Articles in English that focused on randomized controlled trials (RCTs) comparing NOACs (apixaban, dabigatran, and rivaroxaban) with conventional therapy or placebo were abstracted. Independent extraction of relevant data was performed by 2 authors. The primary end point of interest was discontinuation due to all causes. Other end points of interest were discontinuation due to adverse events, consent withdrawal, and nonadherence.ResultsEighteen RCTs including a total of 101,801 patients were included for analysis. Total study drug discontinuation rates were not statistically different with NOACs in comparison to pharmacologically active comparators for treatment of venous thromboembolism/pulmonary embolism (risk ratio [RR], 0.91; 95% CI, 0.74-1.13; P=.40) and for NOACs in comparison to warfarin and aspirin for prevention of stroke in patients with atrial fibrillation (RR, 1.01; 95% CI, 0.87-1.17; P=.92). In contrast, in acute coronary syndromes, total study drug discontinuation with NOACs was significantly higher than with placebo (RR, 1.40; 95% CI, 1.07-1.83; P=.01). Overall discontinuations were comparable to those with active comparators.ConclusionStudy drug discontinuations with NOACs were not significantly different from those with conventional drugs in treatment of venous thromboembolism/pulmonary embolism and prevention of stroke in patients with atrial fibrillation but were worse in acute coronary syndromes as noted in evidence from contemporary RCTs.     

High Risk of Gastrointestinal Hemorrhage in Patients With Epilepsy: A Nationwide Cohort Study

ObjectiveTo examine the association between epilepsy and gastrointestinal hemorrhage.Patients and MethodsWe conducted a nationwide retrospective cohort study by using data from Taiwan’s National Health Insurance Research Database. Patients 20 years and older newly diagnosed as having epilepsy and nonepileptic adults were identified between January 1, 2000, and December 31, 2003, and were observed through December 31, 2008. Cox proportional hazards models were performed to calculate adjusted hazard ratios (HRs) and 95% CIs of gastrointestinal hemorrhage associated with epilepsy.ResultsCompared with the nonepileptic group (n=449,541), epileptic patients (n=1412) had a higher incidence of gastrointestinal hemorrhage (13.4 vs 2.9 per 1000 person-years), with an HR of 2.97 (95% CI, 2.49-3.53). The HRs of gastrointestinal hemorrhage for patients with generalized epilepsy, inpatient care, emergency care, and frequent outpatient visits for epilepsy were 3.50 (95% CI, 2.59-4.72), 3.96 (95% CI, 2.85-5.50), 4.35 (95% CI, 3.15-6.01), and 4.96 (95% CI, 3.97-6.21), respectively. Risks were significantly higher in epileptic patients with mental disorders (HR, 3.20; 95% CI, 2.55-4.01), aged 70 years and older (HR, 4.08; 95% CI, 2.89-5.77), and in the first year after epilepsy (HR, 4.81; 95%, CI, 3.14-7.34).ConclusionEpilepsy is an independent determinant for gastrointestinal hemorrhage in a chronological and severity-dependent pattern. We urge the development of an adequate surveillance policy and strategy for the early prevention of gastrointestinal hemorrhage in epileptic patients.     

Prognostic Value of Exercise Capacity in Patients With Coronary Artery Disease: The FIT (Henry Ford ExercIse Testing) Project

ObjectiveTo examine the prognostic value of exercise capacity in patients with nonrevascularized and revascularized coronary artery disease (CAD) seen in routine clinical practice.Patients and MethodsWe analyzed 9852 adults with known CAD (mean ± SD age, 61±12 years; 69% men [n=6836], 31% black race [n=3005]) from The Henry Ford ExercIse Testing (FIT) Project, a retrospective cohort study of patients who underwent physician-referred stress testing at a single health care system between January 1, 1991, and May 31, 2009. Patients were categorized by revascularization status (nonrevascularized, percutaneous coronary intervention [PCI], or coronary artery bypass graft [CABG] surgery) and by metabolic equivalents (METs) achieved on stress testing. Using Cox regression models, hazard ratios for mortality, myocardial infarction (MI), and downstream revascularizations were calculated after adjusting for potential confounders, including cardiac risk factors, pertinent medications, and stress testing indication.ResultsThere were 3824 all-cause deaths during median follow-up of 11.5 years. In addition, 1880 MIs, and 1930 revascularizations were ascertained. Each 1-MET increment in exercise capacity was associated with a hazard ratio (95% CI) of 0.87 (0.85-0.89), 0.87 (0.85-0.90), and 0.86 (0.84-0.89) for mortality; 0.98 (0.96-1.01), 0.88 (0.84-0.92), and 0.93 (0.90-0.97) for MI; and 0.94 (0.92-0.96), 0.91 (0.88-0.95), and 0.96 (0.92-0.99) for downstream revascularizations in the nonrevascularized, PCI, and CABG groups, respectively. In each MET category, the nonrevascularized group had similar mortality risk as and higher MI and downstream revascularization risk than the PCI and CABG surgery groups (P<.05).ConclusionExercise capacity was a strong predictor of mortality, MI, and downstream revascularizations in this cohort. Furthermore, patients with similar exercise capacities had an equivalent mortality risk, irrespective of baseline revascularization status.     

Relation of Age With Symptom Severity and Quality of Life in Patients With Fibromyalgia

ObjectiveTo examine the relation of age with symptom severity and quality of life (QOL) in patients with fibromyalgia, and to compare physical and mental health of our female patients with those of the US female general population.Patients and MethodsWe studied 978 patients with fibromyalgia from May 1, 2001 through April 30, 2004, and divided them into age groups of young (≤39 years), middle-aged (40-59 years), and older (≥60 years). They completed the Fibromyalgia Impact Questionnaire and the Short Form-36 Health Status Questionnaire (SF-36). Standardized SF-36 physical and mental health summary scores were compared with those of the US female general population of similar age. One-way analysis of variance and post hoc paired t test analyses were performed to detect differences across age groups.ResultsPairwise comparison found young and middle-aged patients having worse fibromyalgia symptoms in all subscales except the anxiety subscale compared with older patients (P≤.01). Similarly, these young and middle-aged patients had worse QOL in the SF-36 mental component summary, as well as SF-36 general health perceptions, vitality, social functioning, and mental health index, compared with older patients (all P<.001). When the QOL of our female patients was compared with that of the US female general population of similar age with standardized SF-36 scores, all age groups had lower QOL in physical, as well as mental, health, with more reduction in physical health, particularly in young patients.ConclusionOur study shows that symptom severity and QOL differ across age groups in patients with fibromyalgia, with young and middle-aged patients having poorer QOL and worse fibromyalgia symptoms than do older patients. QOL in physical health was reduced more than in mental health, particularly in young patients, compared with the general population.     

The Increasing Incidence of Young-Onset Colorectal Cancer: A Call to Action

In the United States, colorectal cancer (CRC) is the third most common and second most lethal cancer. More than one-tenth of CRC cases (11% of colon cancers and 18% of rectal cancers) have a young onset (ie, occurring in individuals younger than 50 years). The CRC incidence and mortality rates are decreasing among all age groups older than 50 years, yet increasing in younger individuals for whom screening use is limited and key symptoms may go unrecognized. Familial syndromes account for approximately 20% of young-onset CRCs, and the remainder are typically microsatellite stable cancers, which are more commonly diploid than similar tumors in older individuals. Young-onset CRCs are more likely to occur in the distal colon or rectum, be poorly differentiated, have mucinous and signet ring features, and present at advanced stages. Yet, stage-specific survival in patients with young-onset CRC is comparable to that of patients with later-onset cancer. Primary care physicians have an important opportunity to identify high-risk young individuals for screening and to promptly evaluate CRC symptoms. Risk modification, targeted screening, and prophylactic surgery may benefit individuals with a predisposing hereditary syndrome or condition (eg, inflammatory bowel disease) or a family history of CRC or advanced adenomatous polyps. When apparently average-risk young adults present with CRC-like symptoms (eg, unexplained persistent rectal bleeding, anemia, and abdominal pain), endoscopic work-ups can expedite diagnosis. Early screening in high-risk individuals and thorough diagnostic work-ups in symptomatic young adults may improve young-onset CRC trends.     

Racial/Ethnic Disparities in Mental Health Over the First 2 Years After Traumatic Brain Injury: A Model Systems Study

ObjectiveTo determine whether racial/ethnic disparities occur in depression, anxiety, and satisfaction with life at 1 and 2 years postdischarge.DesignA prospective, longitudinal, multicenter study of individuals with traumatic brain injury (TBI) participating in the National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems project. Medical, demographic, and outcome data were obtained from the Model Systems database at baseline, as well as 1 and 2 years postdischarge.SettingA total of 16 TBI Model Systems hospitals in the United States.ParticipantsIndividuals with moderate or severe TBI (N=1662) aged 16 years or older consecutively discharged between January 2008 and June 2011 from acute care and comprehensive inpatient rehabilitation at a Model Systems hospital.InterventionNot applicable.Main Outcome MeasuresThe Patient Health Questionnaire-9, Generalized Anxiety Disorder 7-item scale, and Satisfaction with Life Scale assessed depression, anxiety, and satisfaction with life at 1 and 2-year follow-ups.ResultsAfter controlling for all possible covariates, hierarchal linear models found that black individuals had elevated depression across the 2 time points relative to white individuals. Asian/Pacific Islanders' depression increased over time in comparison to the decreasing depression in those of Hispanic origin, which was a greater decrease than in white individuals. Black individuals had lower life satisfaction than did white and Hispanic individuals, but only marginally greater anxiety over time than did white individuals and similar levels of anxiety as did Asian/Pacific Islanders and Hispanic individuals.ConclusionsMental health trajectories of individuals with TBI differed as a function of race/ethnicity across the first 2 years postdischarge, providing the first longitudinal evidence of racial/ethnic disparities in mental health after TBI during this time period. Further research will be required to understand the complex factors underlying these differences.     

Stroke Risk and Outcomes in Patients With Traumatic Brain Injury: 2 Nationwide Studies

ObjectiveTo investigate whether patients with traumatic brain injury (TBI) have an increased risk of stroke or poststroke mortality.Participants and MethodsUsing Taiwan's National Health Insurance Research Database, we conducted a retrospective cohort study of 30,165 patients with new TBI and 120,660 persons without TBI between January 1, 2000, and December 31, 2004. The risk of stroke was compared between 2 cohorts through December 31, 2008. To investigate the association between in-hospital mortality after stroke and history of TBI, we conducted a case-control study of 7751 patients with newly diagnosed stroke between January 1, 2005, and December 31, 2008.ResultsThe TBI cohort had an increased stroke risk (hazard ratio [HR], 1.98; 95% CI, 1.86-2.11). Among patients with stroke, those with a history of TBI had a higher risk of poststroke mortality compared with those without TBI (odds ratio, 1.57; 95% CI, 1.13-2.19). In the TBI cohort, factors associated with stroke were history of TBI hospitalization (HR, 3.14; 95% CI, 2.77-3.56), emergency care for TBI (HR, 3.37; 95% CI, 2.88-3.95), brain hemorrhage (HR, 2.69; 95% CI, 2.43-2.99), skull fracture (HR, 3.00; 95% CI, 2.42-3.71), low income (HR, 2.65; 95% CI, 2.16-3.25), and high medical expenditure for TBI care (HR, 2.26; 95% CI, 2.09-2.43). The severity of TBI was also correlated with poststroke mortality.ConclusionsTraumatic brain injury was associated with risk of stroke and poststroke mortality. The relationship between TBI and poststroke mortality does not seem to transcend all age groups. This research shows the importance of prevention, early recognition, and treatment of stroke in this vulnerable population.     

Biomedical System Dynamics to Improve Anemia Control With Darbepoetin Alfa in Long-Term Hemodialysis Patients

ObjectiveTo determine the value of a biomedical system dynamics (BMSD) approach for optimization of anemia management in long-term hemodialysis patients because elevated hemoglobin levels and high doses of erythropoiesis-stimulating agents (ESAs) may negatively affect survival in this population.Patients and MethodsA model of erythropoiesis and its response to ESAs on the basis of a BMSD method (Mayo Clinic Anemia Management System [MCAMS]) was developed. Thereafter, an open-label, prospective, nonrandomized practice quality improvement project was performed with retrospective analysis in 8 community-based outpatient hemodialysis facilities. All prevalent hemodialysis patients seen from January 1, 2007, through December 31, 2010 (300-342 patients per month), were included with darbepoetin as the ESA. The primary outcome was the percentage of patients who attained the desired hemoglobin level. Secondary outcome measures included the percentage of patients with hemoglobin values above the desired range and mean dose of darbepoetin used.ResultsThe 3 treatment periods were (1) standard ESA protocol in 2007, (2) transition to the MCAMS (2008 to June 2009), and (3) stability period with the MCAMS used in all hemodialysis facilities (2009 to 2010). In the first 6 months of 2007, 69% of patients were in the desired range and 26% were above the range. In comparison, during the first 5 months of 2010, 83% were in and 6% were above the range (P<.001). The mean monthly darbepoetin dose per patient decreased from 304 μg in 2007 to 173 μg by the second half of 2009 (P<.001).ConclusionWith the introduction of the MCAMS, more patients had hemoglobin levels in the desired range and fewer patients exceeded the target range, with a concomitant 40% reduction in darbepoetin use.     

Characterization of a Phenotype-Based Genetic Test Prediction Score for Unrelated Patients With Hypertrophic Cardiomyopathy

ObjectivesTo determine the prevalence and spectrum of mutations and genotype-phenotype relationships in the largest hypertrophic cardiomyopathy (HCM) cohort to date and to provide an easy, clinically applicable phenotype-derived score that provides a pretest probability for a positive HCM genetic test result.Patients and MethodsBetween April 1, 1997, and February 1, 2007, 1053 unrelated patients with the clinical diagnosis of HCM (60% male; mean ± SD age at diagnosis, 44.4±19 years) had HCM genetic testing for the 9 HCM-associated myofilament genes. Phenotyping was performed by review of electronic medical records.ResultsOverall, 359 patients (34%) were genotype positive for a putative HCM-associated mutation in 1 or more HCM-associated genes. Univariate and multivariate analyses identified the echocardiographic reverse curve morphological subtype, an age at diagnosis younger than 45 years, a maximum left ventricular wall thickness of 20 mm or greater, a family history of HCM, and a family history of sudden cardiac death as positive predictors of positive genetic test results, whereas hypertension was a negative predictor. A score, based on the number of predictors of a positive genetic test result, predicted a positive genetic test result ranging from 6% when only hypertension was present to 80% when all 5 positive predictor markers were present.ConclusionIn this largest HCM cohort published to date, the overall yield of genetic testing was 34%. Although all the patients were diagnosed clinically as having HCM, the presence or absence of 6 simple clinical/echocardiographic markers predicted the likelihood of mutation-positive HCM. Phenotype-guided genetic testing using the Mayo HCM Genotype Predictor score provides an easy tool for an effective genetic counseling session.     

A Prospective Pilot Study of Predictors of Acute Stroke in Emergency Department Patients With Dizziness

ObjectiveTo prospectively examine undifferentiated emergency department (ED) patients with dizziness to identify clinical features associated with acute stroke.Patients and MethodsWe conducted a pilot study from November 1, 2009, through October 30, 2010, of adult patients with dizziness presenting to 3 urban academic EDs. Data collected included demographic characteristics, medical history, presenting symptoms, examination findings, clinician pretest probability of stroke, and neuroimaging results. Logistic regression was used to identify variables with a significant association with acute stroke (P<.05).ResultsDuring the study period, we enrolled 473 patients (mean ± SD age, 56.7±19.3 years; 60% female; and 71% white). We found 30 acute, serious diagnoses (6.3%), including 14 ischemic strokes, 2 subarachnoid hemorrhages, 7 mass lesions, 2 demyelinating lesions, 2 severe vertebral artery stenoses, 2 acute coronary syndromes, and 1 case of hydrocephalus and meningitis). We identified 6 clinical variables associated with stroke: age (odds ratio [OR], 1.04; 95% CI, 1.0-1.07), hyperlipidemia (OR, 3.62; 95% CI, 1.24-10.6), hypertension (OR, 4.91; 95% CI, 1.46-16.5), coronary artery disease (OR, 3.33; 95% CI, 1.06-10.5), abnormal tandem gait test result (OR, 3.13; 95% CI, 1.10-8.89), and high or moderate physician pretest probability for acute stroke (OR, 18.8; 95% CI, 4.72-74.5).ConclusionsMost ED patients with dizziness do not have a serious cause of their symptoms. Although the small number of outcomes precluded development of a multivariate model, we identified several individual high-risk variables associated with acute ischemic stroke. Further study will be needed to validate the findings of this pilot investigation.     

The Effect of Resistance Exercise on All-Cause Mortality in Cancer Survivors

ObjectiveTo examine the independent associations of leisure-time aerobic physical activity (PA) and resistance exercise (RE) on all-cause mortality in cancer survivors.Patients and MethodsPatients included 2863 male and female cancer survivors, aged 18 to 81 years, who received a preventive medical examination between April 8, 1987, and December 27, 2002, while enrolled in the Aerobics Center Longitudinal Study in Dallas, Texas. Physical activity and RE were assessed by self-report at the baseline medical examination. Cox proportional hazards regression analysis was performed to determine the independent associations of PA and RE with all-cause mortality in participants who had a history of cancer.ResultsPhysical activity in cancer survivors was not associated with a lower risk of all-cause mortality. In contrast, RE was associated with a 33% lower risk of all-cause mortality (95% CI, 0.45-0.99) after adjusting for potential confounders, including PA.ConclusionIndividuals who participated in RE during cancer survival had a lower risk for all-cause mortality. The present findings provide preliminary evidence for benefits of RE during cancer survival. Future randomized controlled trials examining RE and its effect on lean body mass, muscular strength, and all-cause mortality in cancer survivors are warranted.     

A DPYD Variant (Y186C) Specific to Individuals of African Descent in a Patient With Life-Threatening 5-FU Toxic Effects: Potential for an Individualized Medicine Approach

5-Fluorouracil (5-FU) is commonly administered as a therapeutic agent for the treatment of various aggressive cancers. Severe toxic reactions to 5-FU have been associated with decreased levels of dihydropyrimidine dehydrogenase (DPD) enzyme activity. Manifestations of 5-FU toxicity typically include cytopenia, diarrhea, stomatitis, mucositis, neurotoxicity, and, in extreme cases, death. A variety of genetic variations in DPYD, the gene encoding DPD, are known to result in decreased DPD enzyme activity and to contribute to 5-FU toxic effects. Recently, it was reported that healthy African American individuals carrying the Y186C DPYD variant (rs115232898) had significantly reduced DPD enzyme activity compared with noncarriers of Y186C. Herein, we describe for the first time, to our knowledge, an African American patient with cancer with the Y186C variant who had severe toxic effects after administration of the standard dose of 5-FU chemotherapy. The patient lacked any additional toxic effect–associated variations in the DPYD gene or the thymidylate synthase (TYMS) promoter. This case suggests that Y186C may have contributed to 5-FU toxicity in this patient and supports the use of Y186C as a predictive marker for 5-FU toxic effects in individuals of African ancestry.     

Imaging Pandora's Box: Incidental Findings in Elderly Patients Evaluated for Transcatheter Aortic Valve Replacement

ObjectiveTo determine the frequency and clinical impact of noncardiovascular incidental findings (IFs) detected on preoperative computed tomographic angiography (CTA) of the chest/abdomen/pelvis performed in elderly patients with severe aortic stenosis being considered for transcatheter aortic valve replacement (TAVR).Patients and MethodsThe CTA studies for 424 consecutive patients being evaluated for TAVR between January 1, 2009, through January 24, 2012, were reviewed for noncardiovascular IFs (62.0% male; median ± SD age, 82±8.3 years). The electronic medical record was reviewed to assess for subsequent clinical management and survival.ResultsPotentially pathologic IFs (PPIFs) were present in 285 patients (67.2%). The mean ± SD number of PPIFs per patient was 1.1±1.0 (range, 0-4). Factors associated with higher numbers of PPIFs were reduced ejection fraction (P=.02) and history of smoking (P=.06). Potentially pathologic incidental findings prompted clinical work-up in 39 patients (9.2%) and delayed or canceled treatment plans for aortic stenosis in 7 patients (1.7%). The number needed to image to diagnose a new malignancy or medical condition was 19. The number of PPIFs was predictive of poor overall survival before (hazard ratio, 1.58; 95% CI, 1.31-1.88) and after (hazard ratio, 1.45; 95% CI, 1.19-1.76) adjustment for baseline clinical variables (P<.001 for both).ConclusionThis investigation found that PPIFs are common in elderly patients undergoing TAVR-CTA scans and, once discovered, commonly generate further clinical evaluation. Higher numbers of PPIFs may be predictive of poorer survival, but further study is required to guide the appropriateness of pursuing diagnostic evaluations for asymptomatic PPIFs in this elderly population.     

Long-term Outcome of Globus Pallidus Internus Deep Brain Stimulation in Patients With Tourette Syndrome

ObjectiveTo evaluate the effectiveness of deep brain stimulation (DBS) of the globus pallidus internus (GPi) on tic severity and common comorbidities in patients with severe Tourette syndrome that is refractory to pharmacological treatment and psychotherapy.Patients and MethodsWe retrospectively assessed the long-term clinical outcomes of 13 patients with treatment-refractory Tourette syndrome who underwent DBS targeting the GPi at the Beijing Tiantan Hospital from January 1, 2006, through May 31, 2013. The primary outcome was a change in tic severity as measured by the Yale Global Tic Severity Scale, and the secondary outcome was a change in associated behavioral disorders and mood as measured by the Gilles de la Tourette Syndrome–Quality of Life Scale assessment.ResultsCompared with baseline, the mean reduction in the total Yale Global Tic Severity Scale scores at last follow-up (mean, 41.9 months; range, 13-80 months) was 52.1% (range, 4.3%-83.6%), and the mean improvement rates at 1 month, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 or more months were 11.8%, 20.0%, 26.8%, 36.7%, 44.7%, 49.0%, and 56.7%, respectively. A paired-sample t test revealed significant improvement of tic symptoms after 6 months of DBS programming (P<.05). The Gilles de la Tourette Syndrome–Quality of Life Scale score improved by a mean of 45.7% (range, 11.0%-77.2%).ConclusionThis study is currently the largest reported GPi DBS case series of patients with treatment-refractory TS with the longest follow-up. Our results support the potential beneficial effect of GPi DBS on disabling tic reduction and improvement of quality of life.