Sudden Cardiac Death From the Perspective of Coronary Artery Disease

Sudden cardiac death accounts for approximately 50% of all deaths attributed to cardiovascular disease in the United States. It is most commonly associated with coronary artery disease and can be its initial manifestation or may occur in the period after an acute myocardial infarction. Decreasing the rate of sudden cardiac death requires the identification and treatment of at-risk patients through evidence-based pharmacotherapy and interventional strategies aimed at primary and secondary prevention. For this review, we searched PubMed for potentially relevant articles published from January 1, 1970, through March 1, 2014, using the following key search terms: sudden cardiac death, ischemic heart disease, coronary artery disease, myocardial infarction, and cardiac arrest. Searches were enhanced by scanning bibliographies of identified articles, and those deemed relevant were selected for full-text review. This review outlines various mechanisms for sudden cardiac death in the setting of coronary artery disease, describes risk factors for sudden cardiac death, explores the management of cardiac arrest, and outlines optimal practice for the monitoring and treatment of patients after an acute ST-segment elevation myocardial infarction to decrease the risk of sudden death.     

Nonsteroidal Anti-inflammatory Drugs,Proton Pump Inhibitors,and Gastrointestinal Injury: Contrasting Interactions in the Stomach and Small Intestine

Nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) are among the most frequently prescribed groups of drugs worldwide. The use of NSAIDs is associated with a high number of significant adverse effects. Recently, the safety of PPIs has also been challenged. Capsule endoscopy studies reveal that even low-dose NSAIDs are responsible for gut mucosal injury and numerous clinical adverse effects, for example, bleeding and anemia, that might be difficult to diagnose. The frequent use of PPIs can exacerbate NSAID-induced small intestinal injury by altering intestinal microbiota. Thus, the use of PPI is considered to be an independent risk factor associated with NSAID-associated enteropathy. In this review, we discuss this important clinical problem and review relevant aspects of epidemiology, pathophysiology, and management. We also present the hypothesis that even minor and subclinical injury to the intestinal mucosa can result in significant, though delayed, metabolic consequences, which may seriously affect the health of an individual. PubMed was searched using the following key words (each key word alone and in combination): gut microbiota, microbiome, non-steroidal anti inflammatory drugs, proton pump inhibitors, enteropathy, probiotic, antibiotic, mucosal injury, enteroscopy, and capsule endoscopy. Google engine search was also carried out to identify additional relevant articles. Both original and review articles published in English were reviewed.     

Erdheim-Chester Disease: Characteristics and Management

Erdheim-Chester disease is a rare CD68⁺, CD1a⁻ non-Langerhans cell histiocytosis with multiorgan involvement. The etiology of Erdheim-Chester disease is unclear; there are no known associated infectious or hereditary genetic abnormalities. However, somatic BRAF mutations have recently been identified in these patients. Historically, the literature regarding the management of Erdheim-Chester disease consisted of case reports and small case series with anecdotal therapeutic responses to agents including, but not limited to, cytotoxic chemotherapy, bone marrow transplantation, cladribine, corticosteroids, IFN-α, the BCR-ABL/KIT inhibitor imatinib mesylate, the IL-1 receptor antagonist anakinra, the TNF-inhibitor infliximab, and recently the BRAF inhibitor vemurafenib. We performed a search of the literature using PubMed with the terms Erdheim Chester disease, without date limitations, including case reports, case series, original articles, and previous review articles. In the absence of large-scale studies, experience-based management prevails. The present review details our approach to the management of patients with Erdheim-Chester disease.     

Effect of β-Blockers and Other Antihypertensive Drugs On the Risk of Melanoma Recurrence and Death

ObjectiveTo verify preliminary studies on patients with melanoma exposed to β-blockers that suggested a reduced risk of disease recurrence and death.Patients and MethodsData were obtained from all consecutive patients diagnosed as having melanoma between January 1, 1993, and December 31, 2009, at the Department of Dermatology of the University of Florence, Azienda Sanitaria di Firenze. Participants were excluded if at baseline they reported a previous diagnosis of cutaneous malignant melanoma or another malignant disease. We also excluded participants with evidence of visceral, lymph nodal, and in-transit metastasis at the time of the diagnosis.ResultsOf 741 consecutive patients with melanoma, 79 (11%) were prescribed β-blockers (for hypertension in most cases) for 1 or more years (treated) and 662 (89%) were not (untreated). The multivariate Cox model indicated that the treated group had improved overall survival after a median follow-up of 4 years (P=.005). For each year of β-blocker use, the risk of death was reduced by 38%. The presence of hypertension, the use of antihypertensive agents for 1 or more years, or the use of other commonly used medicines were not associated with a better outcome for patients with melanoma.ConclusionThe results confirm and strengthen previous findings that β-blocker use is associated with a reduced risk of melanoma recurrence and death. The results also indicate the strong need for a randomized clinical trial to conclusively assess whether β-blockers afford protection against melanoma recurrence and death.     

Alcohol and Cardiovascular Health: The Dose Makes the Poison…or the Remedy

Habitual light to moderate alcohol intake (up to 1 drink per day for women and 1 or 2 drinks per day for men) is associated with decreased risks for total mortality, coronary artery disease, diabetes mellitus, congestive heart failure, and stroke. However, higher levels of alcohol consumption are associated with increased cardiovascular risk. Indeed, behind only smoking and obesity, excessive alcohol consumption is the third leading cause of premature death in the United States. Heavy alcohol use (1) is one of the most common causes of reversible hypertension, (2) accounts for about one-third of all cases of nonischemic dilated cardiomyopathy, (3) is a frequent cause of atrial fibrillation, and (4) markedly increases risks of stroke—both ischemic and hemorrhagic. The risk-to-benefit ratio of drinking appears higher in younger individuals, who also have higher rates of excessive or binge drinking and more frequently have adverse consequences of acute intoxication (for example, accidents, violence, and social strife). In fact, among males aged 15 to 59 years, alcohol abuse is the leading risk factor for premature death. Of the various drinking patterns, daily low- to moderate-dose alcohol intake, ideally red wine before or during the evening meal, is associated with the strongest reduction in adverse cardiovascular outcomes. Health care professionals should not recommend alcohol to nondrinkers because of the paucity of randomized outcome data and the potential for problem drinking even among individuals at apparently low risk. The findings in this review were based on a literature search of PubMed for the 15-year period 1997 through 2012 using the search terms alcohol, ethanol, cardiovascular disease, coronary artery disease, heart failure, hypertension, stroke, and mortality. Studies were considered if they were deemed to be of high quality, objective, and methodologically sound.     

Diagnosis and Management of Benign,Atypical, and Indeterminate Breast Lesions Detected on Core Needle Biopsy

Imaging abnormalities detected by mammographic screening often lead to diagnostic evaluations, with suspicious abnormalities subjected to image-guided core needle biopsy (CNB) to exclude malignancy. Most CNBs reveal benign pathological alterations, termed benign breast disease (BBD). Adoption of CNB presents challenges with pathologic classification of breast abnormalities and management of patients with benign or atypical histological findings. Patient management and counseling after CNB diagnosis of BBD depends on postbiopsy determination of radiologic-pathologic concordancy. Communication between radiologists and pathologists is crucial in patient management. Management is dependent on the histological type of BBD. Patients with concordant pathologic imaging results can be reassured of benign biopsy findings and advised about the future risk of developing breast cancer. Surgical consultation is advised for patients with discordant findings, symptomatic patients, and high-risk lesions. This review highlights benign breast lesions that are encountered on CNB and summarizes management strategies. For this review, we conducted a search of PubMed, with no date limitations, and used the following search terms (or a combination of terms): atypical ductal hyperplasia, atypical hyperplasia, atypical lobular hyperplasia, benign breast disease, cellular fibroepithelial lesions, columnar cell lesions, complex sclerosing lesion, core needle biopsy, fibroadenomas, flat epithelial atypia, lobular carcinoma in situ, lobular neoplasia, mucocele-like lesions, phyllodes tumor, pseudoangiomatous stromal hyperplasia, radial scar, and vascular lesions. The selection of references included in this review was based on study relevance and quality. We used additional articles culled from the bibliographies of retrieved articles to examine the published evidence for risk factors of BBD.     

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.     

Clinical and Histologic Findings in Patients With Uveal Melanomas After Taking Tumor Necrosis Factor-α Inhibitors

ObjectiveTo describe the progression of uveal melanocytic lesions to melanomas after initiation of tumor necrosis factor-α (TNF-α) inhibitors.Patients and MethodsWe report 3 cases of uveal melanoma occurring after treatment with TNF-α inhibitors, 2 from Mayo Clinic and 1 from Yale University. The study took place from February 27, 2009, through July 15, 2013.ResultsTwo women and one man with inflammatory disease who received TNF-α inhibitors had subsequent development of uveal melanomas. The 2 women had inflammatory bowel disease and had been followed up for melanocytic tumors that grew markedly within 1 year after beginning treatment with TNF-α inhibitors to the point of requiring treatment. One had histologic confirmation of the melanoma. The male patient had rheumatoid arthritis that was being treated with TNF-α inhibitors. Serial ultrasonography was performed to monitor bilateral diffuse scleritis, and within 16 months of initiation of TNF-α inhibitor therapy, a choroidal mass was detected that continued to grow over the next 3 months. The patient elected to have enucleation, which revealed uveal melanoma and thinning of the sclera from the previous scleritis.ConclusionOur 3 cases of uveal melanocytic tumors occurring after the use of TNF-α inhibitors add to the growing literature suggesting a correlation between TNF-α inhibitors and the development of malignant neoplasms. Considering the association between cutaneous melanoma and TNF-α inhibitors, we recommend that patients have an eye examination before initiation of TNF-α inhibitors, and those with preexisting nevi should be followed up at regular intervals.     

Multiple Sclerosis: Current and Emerging Disease-Modifying Therapies and Treatment Strategies

Multiple sclerosis (MS) is a chronic inflammatory demyelinating central nervous system disease that typically strikes young adults, especially women. The pathobiology of MS includes inflammatory and neurodegenerative mechanisms that affect both white and gray matter. These mechanisms underlie the relapsing, and often eventually progressive, course of MS, which is heterogeneous; confident prediction of long-term individual prognosis is not yet possible. However, because revised MS diagnostic criteria that incorporate neuroimaging data facilitate early diagnosis, most patients are faced with making important long-term treatment decisions, most notably the use and selection of disease-modifying therapy (DMT). Currently, there are 10 approved MS DMTs with varying degrees of efficacy for reducing relapse risk and preserving neurological function, but their long-term benefits remain unclear. Moreover, available DMTs differ with respect to the route and frequency of administration, tolerability and likelihood of treatment adherence, common adverse effects, risk of major toxicity, and pregnancy-related risks. Thorough understanding of the benefit-risk profiles of these therapies is necessary to establish logical and safe treatment plans for individuals with MS. We review the available evidence supporting risk-benefit profiles for available and emerging DMTs. We also assess the place of individual DMTs within the context of several different MS management strategies, including those currently in use (sequential monotherapy, escalation therapy, and induction and maintenance therapy) and others that may soon become feasible (combination approaches and “personalized medicine”). We conducted this review using a comprehensive search of MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials, from January 1, 1990, to August 31, 2013. The following search terms were used: multiple sclerosis, randomized controlled trials, interferon-beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, BG-12, alemtuzumab, rituximab, ocrelizumab, daclizumab, neutralizing antibodies, progressive multifocal leukoencephalopathy.     

Pseudomonas aeruginosa injection enhanced antitumor cytotoxicity of cytokine-induced killer cells derived from cord blood

Cord blood (CB) is becoming an extensive source of cytokine-induced killer cells. It had been used in several clinical settings and proven to be efficacious and safe. Therefore, we investigated the possibility of combining CIK cells derived from cord blood (CB-CIK) and Pseudomonas aeruginosa injection (PA-MSHA) in order to enhance the cytotoxicity of CB-CIK cells against tumors. Compared with the CB-CIK cells, the PA-MSHA-treated CB-CIK cells demonstrated with increased proliferation rates, higher expression of activated cell surface marker CD28 and lower expression of inhibited cell surface markers PD-1 and CTLA-4. Furthermore, PA-MSHA-treated CB-CIK cells exhibited more effectively for secreting pro-inflammatory cytokine such as IFN-γ and expressing high levels of TLR2, TLR4 and TLR6. The expression of CD107a was higher in the CD3⁺CD56⁺ subset of PA-MSHA-treated CB-CIK cells. Our results indicate that the PA-MSHA-treated CB-CIK cells exhibited a more potent in cytotoxic activity against tumor cells. Thus, PA-MSHA enhanced the antitumor ability of CB-CIK cells.     

Hypoglycemia,Chronic Kidney Disease,and Diabetes Mellitus

Hypoglycemia is a major problem associated with substantial morbidity and mortality in patients with diabetes and is often a major barrier to achieving optimal glycemic control. Chronic kidney disease not only is an independent risk factor for hypoglycemia but also augments the risk of hypoglycemia that is already present in people with diabetes. This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetes and chronic kidney disease and reviews therapeutic considerations in this situation. PubMed and MEDLINE were searched for literature published in English from January 1989 to May 2014 for diabetes mellitus, hypoglycemia, chronic kidney disease, and chronic renal insufficiency.     

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.     

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.     

Update on Intravenous Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke

The controversial field of interventional stroke neurology has attracted considerable interest within the stroke community, but no endovascular interventional therapies have proved to be superior to intravenous (IV) recombinant tissue plasminogen activator (rtPA), the standard of care for patients with acute ischemic stroke. In this article, we review the evidence and background of IV thrombolysis for stroke, the clinical application of IV rtPA in practice, and the management of potential complications after thrombolysis. We conducted this review using a search of PubMed for articles published from January 1, 1995, to October 31, 2013, with the following terms: ischemic stroke, tissue plasminogen activator, TPA, alteplase, thrombolysis, and intracranial hemorrhage. Articles were also identified through searches of reference lists and the authors’ files. In nearly 2 decades since the publication of the transformative National Institute of Neurological Disorders and Stroke trials, the efficacy and safety of IV rtPA has been consistently verified in international real-world clinical practice. Time from stroke symptom onset to thrombolysis is crucial and probably the most important determinant of success of IV therapy. Thus, optimal care of patients with acute stroke should include community education and standardized protocols to guide immediate patient assessment and triage to medical centers with capability for efficient neurologic assessment, brain imaging, drug administration, and specialized postthrombolysis care.     

Controversies in Barrett Esophagus

Barrett esophagus develops when metaplastic columnar epithelium predisposed to develop adenocarcinoma replaces esophageal squamous epithelium damaged by gastroesophageal reflux disease. Although several types of columnar metaplasia have been described in Barrett esophagus, intestinal metaplasia with goblet cells currently is required for a definitive diagnosis in the United States. Studies indicate that the risk of adenocarcinoma for patients with nondysplastic Barrett esophagus is only 0.12% to 0.38% per year, which is substantially lower than previous studies had suggested. Nevertheless, the incidence of esophageal adenocarcinoma continues to rise at an alarming rate. Regular endoscopic surveillance for dysplasia is the currently recommended cancer prevention strategy for Barrett esophagus, but a high-quality study has found no benefit of surveillance in preventing deaths from esophageal cancer. Medical societies currently recommend endoscopic screening for Barrett esophagus in patients with multiple risk factors for esophageal adenocarcinoma, including chronic gastroesophageal reflux disease, age of 50 years or older, male sex, white race, hiatal hernia, and intra-abdominal body fat distribution. However, because the goal of screening is to identify patients with Barrett esophagus who will benefit from endoscopic surveillance and because such surveillance may not be beneficial, the rationale for screening might be made on the basis of faulty assumptions. Endoscopic ablation of dysplastic Barrett metaplasia has been reported to prevent its progression to cancer, but the efficacy of endoscopic eradication of nondysplastic Barrett metaplasia as a cancer preventive procedure is highly questionable. This review discusses some of these controversies that affect the physicians and surgeons who treat patients with Barrett esophagus. Studies relevant to controversial issues in Barrett esophagus were identified using PubMed and relevant search terms, including Barrett esophagus, ablation, dysplasia, radiofrequency ablation, and endoscopic mucosal resection.     

Idiopathic Pulmonary Fibrosis: Evolving Concepts

Idiopathic pulmonary fibrosis (IPF) occurs predominantly in middle-aged and older adults and accounts for 20% to 30% of interstitial lung diseases. It is usually progressive, resulting in respiratory failure and death. Diagnostic criteria for IPF have evolved over the years, and IPF is currently defined as a disease characterized by the histopathologic pattern of usual interstitial pneumonia occurring in the absence of an identifiable cause of lung injury. Understanding of the pathogenesis of IPF has shifted away from chronic inflammation and toward dysregulated fibroproliferative repair in response to alveolar epithelial injury. Idiopathic pulmonary fibrosis is likely a heterogeneous disorder caused by various interactions between genetic components and environmental exposures. High-resolution computed tomography can be diagnostic in the presence of typical findings such as bilateral reticular opacities associated with traction bronchiectasis/bronchiolectasis in a predominantly basal and subpleural distribution, along with subpleural honeycombing. In other circumstances, a surgical lung biopsy may be needed. The clinical course of IPF can be unpredictable and may be punctuated by acute deteriorations (acute exacerbation). Although progress continues in unraveling the mechanisms of IPF, effective therapy has remained elusive. Thus, clinicians and patients need to reach informed decisions regarding management options including lung transplant. The findings in this review were based on a literature search of PubMed using the search terms idiopathic pulmonary fibrosis and usual interstitial pneumonia, limited to human studies in the English language published from January 1, 2000, through December 31, 2013, and supplemented by key references published before the year 2000.     

Role of Dietary Salt and Potassium Intake in Cardiovascular Health and Disease: A Review of the Evidence

The objective of this review was to provide a synthesis of the evidence on the effect of dietary salt and potassium intake on population blood pressure, cardiovascular disease, and mortality. Dietary guidelines and recommendations are outlined, current controversies regarding the evidence are discussed, and recommendations are made on the basis of the evidence. Designed search strategies were used to search various databases for available studies. Randomized trials of the effect of dietary salt intake reduction or increased potassium intake on blood pressure, target organ damage, cardiovascular disease, and mortality were included. Fifty-two publications from January 1, 1990, to January 31, 2013, were identified for inclusion. Consideration was given to variations in the search terms used and the spelling of terms so that studies were not overlooked, and search terms took the following general form: (dietary salt or dietary sodium or [synonyms]) and (dietary potassium or [synonyms]) and (blood pressure or hypertension or vascular disease or heart disease or chronic kidney disease or stroke or mortality or [synonyms]). Evidence from these studies demonstrates that high salt intake not only increases blood pressure but also plays a role in endothelial dysfunction, cardiovascular structure and function, albuminuria and kidney disease progression, and cardiovascular morbidity and mortality in the general population. Conversely, dietary potassium intake attenuates these effects, showing a linkage to reduction in stroke rates and cardiovascular disease risk. Various subpopulations, such as overweight and obese individuals and aging adults, exhibit greater sensitivity to the effects of reduced salt intake and may gain the most benefits. A diet that includes modest salt restriction while increasing potassium intake serves as a strategy to prevent or control hypertension and decrease cardiovascular morbidity and mortality. Thus, the body of evidence supports population-wide sodium intake reduction and recommended increases in dietary potassium intake as outlined by current guidelines as an essential public health effort to prevent kidney disease, stroke, and cardiovascular disease.     

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.     

Psychiatric Adverse Effects of Pediatric Corticosteroid Use

Corticosteroids, highly effective drugs for myriad disease states, have considerable neuropsychiatric adverse effects that can manifest in cognitive disorders, behavioral changes, and frank psychiatric disease. Recent reviews have summarized these effects in adults, but a comprehensive review on corticosteroid effects in children has not been published since 2005. Here, we systematically review articles published since then that, we find, naturally divide into 3 main areas: (1) chronic effects of acute prenatal and neonatal exposure associated with prematurity and congenital conditions; (2) immediate behavioral effects of acute exposure via oncological protocols; and (3) acute behavioral effects of sporadic use in children and adolescents with other conditions. PsycInfo, MEDLINE, Embase, and Scopus were queried to identify articles reporting psychiatric adverse effects of corticosteroids in pediatric patients. Search terms included corticosteroids, adrenal cortex hormones, steroid psychosis, substance-induced psychoses, glucocorticoids, dexamethasone, hydrocortisone, prednisone, adverse effects, mood disorders, mental disorders, psychosis, psychotic, psychoses, side effect, chemically induced, emotions, affective symptoms, toxicity, behavior, behavioral symptoms, infant, child, adolescent, pediatric, paediatric, neonatal, children, teen, and teenager. Following guidelines for systematic reviews from the Potsdam Consultation on Meta-Analysis, we have found it difficult to draw specific conclusions that are more than general impressions owing to the quality of the available studies. We find a mixed picture with neonates exposed to dexamethasone, with some articles reporting eventual deficits in neuropsychiatric functioning and others reporting no effect. In pediatric patients with acute lymphoblastic leukemia, corticosteroid use appears to correlate with negative psychiatric and behavioral effects. In children treated with corticosteroids for noncancer conditions, adverse effects have been observed both during treatment and after cessation, although the data from article to article are not consistent enough to establish dose relationships. By and large, inhaled corticosteroids are considered safe and free of severe neuropsychiatric effects. Although both antipsychotic medications and benzodiazepines have been used to treat corticosteroid-induced mania and psychosis, no unified management strategy has emerged. Large-scale standardized investigations are needed to clarify the psychiatric effect of corticosteroids on children in all these conditions. Meanwhile, there is general agreement that patients as well as caregivers should be warned of the potential for behavioral adverse effects when patients receive these drugs.     

Serum Polyclonal Immunoglobulin Free Light Chain Levels Predict Mortality in People With Chronic Kidney Disease

ObjectiveTo determine whether elevated serum polyclonal free light chain (FLC) levels predict mortality in a population of individuals with chronic kidney disease (CKD).Patients and MethodsFrom January 2, 2006, through July 31, 2007, we recruited a cohort of 848 people with CKD who were not receiving renal replacement therapy and did not have monoclonal gammopathy. We measured serum kappa FLC and lambda FLC isotype levels to determine combined FLC (cFLC) levels. The cohort was prospectively followed up for a median of 63 months (interquartile range, 0-93 months). Cox regression analysis was performed to determine variables predictive of mortality.ResultsHigh cFLC levels were an independent risk factor for death (hazard ratio [HR], 2.71; 95% CI, 1.98-3.70; P<.001). Other independent risk factors were age (HR, 1.79; 95% CI, 1.52-2.10; P<.001), South Asian ethnicity (HR, 0.33; 95% CI, 0.14-0.64; P=.02), preexisting cardiovascular disease (HR, 1.59; 95% CI, 1.09-2.31; P=.02), and high-sensitivity C-reactive protein (HR, 1.13; 95% CI, 1.00-1.28; P=.04). Neither estimated glomerular filtration rate nor albuminuria was an independent risk factor for death.ConclusionHigh cFLC levels independently predict mortality in people with CKD.