Reporting of serious adverse events during cancer clinical trials to the institutional review board: an evaluation by the research on adverse drug events and reports (RADAR) project.

Global introspection is considered an unreliable method for attribution of causality of serious adverse events (SAEs), yet remains widely used for cancer drug clinical trials. Here, we compare structured case abstraction (SCA) to the routine method for detecting, evaluating, and reporting ADEs during cancer drug clinical trials to an Institutional Review Board (IRB). We obtained all SAE reports (2001-2008) received by one IRB for six clinical trials involving bevacizumab or oxaliplatin for treatment of gastrointestinal cancers. We compared the routine IRB SAE method to SCA for adverse event detection and causality attribution. Of 205 adverse events, 182 events (75%) were not reported; of these, 6 (20%) of 30 SAEs requiring an IRB report were unreported. For the 10 item Naranjo score, the amount of information useful for causality attribution was higher with SCA than the routine method (6.0 vs. 2.4 items, P < .0001). One-fifth of SAEs requiring an IRB report were unreported to the IRB via the routine method. SCA provided more useful information as to whether an SAE was caused by a cancer drug exposure. Our results suggest that SCA may improve SAE detection and the accuracy of attribution of causality during cancer drug clinical trials.

Quality of methods for assessing and reporting serious adverse events in clinical trials of cancer drugs.

The validity of information regarding drug toxicity in humans depends on the quality of the methods and instruments used to assess adverse drug events (ADEs). This study evaluates the quality of instruments used to assess and report ADEs to institutional review boards (IRBs) at US cancer centers. Forms from all 49 National Cancer Institute (NCI)-designated centers were assessed for utility in abstracting event type, severity, and causality; patient demographics; safety monitoring; and consequent changes in the conduct of the relevant study. Of the 55 items considered essential for ADE reporting, one item (event description) was present on all the forms. Seventy-eight percent of the instruments prompted for global introspection of the investigator, a method known to be unreliable. Of the 34 items that our panel of experts considered essential for event description, the median number of items present was four (domain = 1-11). The use of a validated tool to describe and assess event type, severity, and causality may lead to more timely, accurate identification of safety signals in cancer treatment.

Application of software design principles and debugging methods to an analgesia prescription reduces risk of severe injury from medical use of opioids.

A prescription is a health-care program implemented by a physician or other qualified practitioner in the form of instructions that govern the plan of care for an individual patient. Although the algorithmic nature of prescriptions is axiomatic, this insight has not been applied systematically to medication safety. We used software design principles and debugging methods to create a "Patient-oriented Prescription for Analgesia" (POPA), assessed the rate and extent of adoption of POPA by physicians, and conducted a statistical process control clinical trial and a subsidiary cohort analysis to evaluate whether POPA would reduce the rate of severe and fatal opioid-associated adverse drug events (ADEs). We conducted the study in a population of 153,260 hospitalized adults, 50,576 (33%) of whom received parenteral opioids. Hospitalwide, the use of POPA increased to 62% of opioid prescriptions (diffusion half-life = 98 days), while opioid-associated severe/fatal ADEs fell from an initial peak of seven per month to zero per month during the final 6 months (P < 0.0016) of the study. In the nested orthopedics subcohort, the use of POPA increased the practice of recording pain scores (94% vs. 72%, P < 0.00001) and the use of adjuvant analgesics (95% vs. 40%, P < 0.00001) and resulted in fewer opioid-associated severe ADEs than routine patient-controlled analgesia (PCA) (0% vs. 2.7%, number needed to treat (NNT) = 35, P < 0.015). The widespread diffusion of POPA was associated with a substantial hospitalwide decline in opioid-associated severe/fatal ADEs.

Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem-cell transplants or intensive chemotherapy.

Zygomycosis is increasingly reported as a cause of life-threatening fungal infections. A higher proportion of cases reported over the last decades have been in cancer patients, with or without hematopoietic stem cell transplantation (HSCT). The new anti-fungal agent voriconazole is a recently identified risk factor for developing zygomycosis. We reviewed the clinical characteristics and outcomes of a large cohort of cancer patients who developed zygomycosis after exposure to voriconazole. Health care professionals at 13 large cancer centers provided clinical information on cancer patients with zygomycosis and prior exposure to voriconazole. Criteria for inclusion were 5 days or more of voriconazole use and diagnostic confirmation with tissue or histology. Fifty-eight cases were identified among patients with hematologic malignancies, 62% including patients who underwent a HSCT procedure. Fifty-six patients received voriconazole for primary or secondary prophylaxis against fungal infection. In addition to prior exposure to voriconazole, patients also had several of the previously established risk factors for zygomycosis. Amphotericin B was the most commonly prescribed anti-fungal therapy. Overall mortality was 73%. We conclude that zygomycosis after exposure to voriconazole is a recently described entity that is frequently fatal, despite treatment with currently available anti-fungal agents and surgery.

HIV-related Pneumocystis carinii pneumonia in older patients hospitalized in the early HAART era.

OBJECTIVE: To determine whether older age continues to influence patterns of care and in-hospital mortality for hospitalized persons with HIV-related Pneumocystis carinii pneumonia (PCP), as determined in our prior study from the 1980s. DESIGN: Retrospective chart review. PATIENTS/SETTING: Patients (1,861) with HIV-related PCP at 78 hospitals in 8 cities from 1995 to 1997. MEASUREMENTS: Medical record notation of possible HIV infection; alveolar-arterial oxygen gradient; CD4 lymphocyte count; presence or absence of wasting; timely use of anti-PCP medications; in-hospital mortality. MAIN RESULTS: Compared to younger patients, patients > or =50 years of age were less likely to have HIV mentioned in their progress notes (70% vs 82%, P <.001), have mild or moderately severe PCP cases at admission (89% vs 96%, P <.002), receive anti-PCP medications within the first 2 days of hospitalization (86% vs 93%, P <.002), and survive hospitalization (82% vs 90%, P <.003). However, age was not a significant predictor of mortality after adjustment for severity of PCP and timeliness of therapy. CONCLUSIONS: While inpatient PCP mortality has improved by 50% in the past decade, 2-fold age-related mortality differences persist. As in the 1980s, these differences are associated with lower rates of recognition of HIV, increased severity of illness at admission, and delays in initiation of PCP-specific treatments among older individuals--factors suggestive of delayed recognition of HIV infection, pneumonia, and PCP, respectively. Continued vigilance for the possibility of HIV and HIV-related PCP among persons > or =50 years of age who present with new pulmonary symptoms should be encouraged.

Efficacy of endoscopic sinus surgery in the management of patients with asthma and chronic sinusitis.

An association between chronic sinusitis and asthma has been noted for many years, although the precise nature of the relationship is poorly understood. Earlier studies, using traditional surgical techniques, have demonstrated subjective improvement in asthmatic complaints. Reports demonstrating improvement following endoscopic sinus surgery for chronic sinusitis are rare. To report our experience with endoscopic sinus surgery and asthmatics, we reviewed the charts of 75 consecutive patients with asthma and chronic sinusitis who underwent endoscopic sinus surgery between 1994 and 1996. Study criteria included the following: chronic sinusitis, one year preoperative and one year postoperative follow-up from endoscopic sinus surgery, and asthma requiring inhaled steroids and oral prednisone for control. Many patients required prednisone bursts for control of asthma. Number of days and total dose of oral prednisone were used as objective measures of asthma control. Number of weeks of antibiotics was used as a relative measure of sinusitis. Fourteen of the 15 patients meeting study criteria decreased their postoperative prednisone requirement by total number of days (preoperative 84 versus postoperative 63 days [p < 0.0001]). Postoperatively, patients required an average of 1300 mg less oral prednisone (p < 0.033). Antibiotic use also decreased, with an average use of antibiotic nine weeks preoperatively versus seven weeks postoperatively (p < 0.045). This study provides corroborative objective evidence that, at least in the short term, endoscopic sinus surgery is efficacious in the management of patients with chronic sinusitis and asthma.

Parental knowledge and practice of primary skin cancer prevention: gaps and solutions.

Over the past two decades there have been significant efforts in the United States to heighten awareness about skin cancer. Our goal was to assess parental knowledge, practice, and source of information about sun protection for their children. A questionnaire was administered to 158 parents of children at a dermatology clinic and 96 parents of children at a pediatric clinic (n=254). The survey included four parts: demographics, knowledge about skin cancer, sun protection practices, and sources of sun protection information. The mean knowledge score was 61% correct. Independent predictors of a higher score were fewer children and being a health care or other professional (p < 0.03). Independent predictors of parental sunscreen use were higher knowledge score, younger age, and fewer lifetime sunburns (p < 0.03); predictors of sunscreen use for children were higher knowledge score and fairer skin (p < 0.03). The top sources of sun protection information ranked by respondents were television and magazines; the top desired sources were primary care physicians and dermatologists. The knowledge results suggest the need for increased education about skin cancer prevention. Because the media is a major information source, it is important to ensure that messages about sun risks/protection are correct. The respondents' desire to learn more from primary care physicians emphasizes the need to educate physicians about sun protection.

Human leucocyte antigens (HLA) and trimellitic anhydride (TMA) immunological lung disease.

Occupational immunological lung disease, due to low molecular weight, reactive chemicals such as trimellitic anhydride (TMA), is an emerging health problem. If there were a marker that was highly predictive of the ability of the immune system to recognize TMA as an allergen, better prevention strategies could be employed with at risk individuals. The purpose of this study is to evaluate whether human leucocyte antigen (HLA) class specificity is associated with the development of late respiratory systemic syndrome (LRSS) or asthma due to immunological sensitivity to trimellitic anhydride (TMA). This is a case control study of 17 individuals with LRSS, 12 with asthma and 22 TMA similarly exposed individuals who did not develop LRSS or asthma. Comparing the sensitized individuals (LRSS or asthma) with the non-sensitized individuals (controls), we found no difference in frequency of any HLA antigen. In summary, the lack of association of HLA antigens with LRSS or asthma due to TMA suggests that these will not be useful markers to identify at risk individuals.

Multicenter, double-blind, placebo-controlled, multiple-challenge evaluation of reported reactions to monosodium glutamate.

BACKGROUND: The frequency of reactions reported to occur after the consumption of monosodium glutamate (MSG) is the subject of controversy. OBJECTIVE: We conducted a multicenter, multiphase, double-blind, placebo-controlled study with a crossover design to evaluate reactions reportedly caused by MSG. METHODS: In 3 of 4 protocols (A, B, and C), MSG was administered without food. A positive response was scored if the subject reported 2 or more symptoms from a list of 10 symptoms reported to occur after ingestion of MSG-containing foods within 2 hours. In protocol A 130 self-selected reportedly MSG-reactive volunteers were challenged with 5 g of MSG and with placebo on separate days (days 1 and 2). Of the 86 subjects who reacted to MSG, placebo, or both in protocol A, 69 completed protocol B to determine whether the response was consistent and dose dependent. To further examine the consistency and reproducibility of reactions to MSG, 12 of the 19 subjects who responded to 5 g of MSG but not to placebo in both protocols A and B were given, in protocol C, 2 challenges, each consisting of 5 g of MSG versus placebo. RESULTS: Of 130 subjects in protocol A, 50 (38. 5%) responded to MSG only, 17 (13.1%) responded to placebo only (P <. 05), and 19 (14.6%) responded to both. Challenge with increasing doses of MSG in protocol B was associated with increased response rates. Only half (n = 19) of 37 subjects who reacted to 5 g of MSG but not placebo in protocol A reacted similarly in protocol B, suggesting inconsistency in the response. Two of the 19 subjects responded in both challenges to MSG but not placebo in protocol C; however, their symptoms were not reproducible in protocols A through C. These 2 subjects were challenged in protocol D 3 times with placebo and 3 times with 5 g of MSG in the presence of food. Both responded to only one of the MSG challenges in protocol D. CONCLUSION: The results suggest that large doses of MSG given without food may elicit more symptoms than a placebo in individuals who believe that they react adversely to MSG. However, neither persistent nor serious effects from MSG ingestion are observed, and the responses were not consistent on retesting.

Improvements in outcomes of acute respiratory failure for patients with human immunodeficiency virus-related Pneumocystis carinii pneumonia.

In the early 1990s, hospital survival among patients with human immunodeficiency virus (HIV)-related Pneumocystis carinii pneumonia (PCP) and respiratory failure was poor, approximately 20%. We examined ICU use and outcomes for patients with acute respiratory failure from PCP from 1995 to 1997. We conducted a retrospective medical record review using a random sample of 71 hospitals in seven regions of the United States. Among 1,660 patients with confirmed or presumed PCP, 155 (9%) received mechanical ventilation for respiratory failure. Factors that predicted use of mechanical ventilation, independent of severity of illness on hospital admission, included African-American ethnicity and geographic location (p

IL-1beta and TNF-alpha in prostatic secretions are indicators in the evaluation of men with chronic prostatitis.

PURPOSE: Chronic Prostatitis, or Chronic Pelvic Pain Syndrome [CPPS], is a common disorder characterized by pelvic pain and varying degrees of inflammation in expressed prostatic secretions (EPS). In search of markers to more clearly define CPPS, we compared proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) levels in EPS from men with CPPS, to healthy men and men with Benign Prostatic Hyperplasia (BPH). METHODS: 78 men: controls (n = 16), BPH (n = 14), CPPS IIIA [>/=10 white blood cells per high power field (WBC/hpf) in EPS] (n = 18), CPPS IIIB [<10 WBC/hpf in EPS] (n = 20), and asymptomatic inflammatory prostatitis (AIP) (n = 10) were evaluated for EPS WBC, and IL-1beta and TNF-alpha by ELISA. RESULTS: IL-1beta and TNF-alpha levels in EPS were usually detectable in men with CPPS IIIA (89% and 45%, respectively) or AIP (90%; 100%), but less often in controls (31%; 17%), BPH (57%; 15%), and CPPS IIIB (35%; 15%) respectively. IL-1beta and TNF-alpha levels were higher in CPPS IIIA versus CPPS IIIB, and in AIP versus controls or BPH (p's <0.001). Cut-points for IL-1beta and TNF-alpha discriminated AIP from controls (predictive values = 94% and 83%, respectively) and CPPS IIIA from CPPS IIIB (predictive values 84% and 100%). Overall, there was a correlation between IL-1beta and TNF-alpha (p <0.003), but no correlation between WBC and IL-1beta (p <0.1) or TNF-alpha (p <0.50). CONCLUSIONS: Cytokines are frequently present and elevated in the EPS from men with CPPS IIIA and AIP and provide a novel means for identification, characterization and potential management of men with CPPS that differs from traditional methods based on WBC.

A new preadmission staging system for predicting inpatient mortality from HIV-associated Pneumocystis carinii pneumonia in the early highly active antiretroviral therapy (HAART) era.

A common severe complication of human immunodeficiency virus (HIV) infection has been Pneumocystis carinii pneumonia (PCP). Recently, with increasing use of PCP prophylaxis and multidrug antiretroviral therapy, the clinical manifestations of HIV infection have changed dramatically and the predictors of inpatient mortality for PCP may have also changed. We developed a new staging system for predicting inpatient mortality for patients with HIV-associated PCP admitted between 1995 and 1997. Trained abstractors performed chart reviews of 1,660 patients hospitalized with HIV-associated PCP between 1995 and 1997 at 78 hospitals in seven metropolitan areas in the United States. The overall inpatient mortality rate was 11.3%. Hierarchically optimal classification tree analysis identified an ordered five-category staging system based on three predictors: wasting, alveolar-arterial oxygen gradient (AaPO(2)), and serum albumin level. The mortality rate increased with stage: 3.7% for Stage 1, 8.5% for Stage 2, 16.1% for Stage 3, 23.3% for Stage 4, and 49.1% for Stage 5. This new staging system may be useful for severity of illness adjustment in the current era while exploring current variation in HIV-associated PCP inpatient mortality rates among hospitals and across cities.

Review of alleged reaction to monosodium glutamate and outcome of a multicenter double-blind placebo-controlled study.

Monosodium glutamate (MSG) has a long history of use in foods as a flavor enhancer. In the United States, the Food and Drug Administration has classified MSG as generally recognized as safe (GRAS). Nevertheless, there is an ongoing debate exists concerning whether MSG causes any of the alleged reactions. A complex of symptoms after ingestion of a Chinese meal was first described in 1968. MSG was suggested to trigger these symptoms, which were referred to collectively as Chinese Restaurant Syndrome. Numerous reports, most of them anecdotal, were published after the original observation. Since then, clinical studies have been performed by many groups, with varying degrees of rigor in experimental design ranging from uncontrolled open challenges to double-blind, placebo controlled (DBPC) studies. Challenges in subjects who reported adverse reactions to MSG have included relatively few subjects and have failed to show significant reactions to MSG. Results of surveys and of clinical challenges with MSG in the general population reveal no evidence of untoward effects. We recently conducted a multicenter DBPC challenge study in 130 subjects (the largest to date) to analyze the response of subjects who report symptoms from ingesting MSG. The results suggest that large doses of MSG given without food may elicit more symptoms than a placebo in individuals who believe that they react adversely to MSG. However, the frequency of the responses was low and the responses reported were inconsistent and were not reproducible. The responses were not observed when MSG was given with food.

Substance use disorder in hospitalized severely mentally ill psychiatric patients: prevalence, correlates, and subgroups.

The prevalence and demographic and clinical correlates of lifetime substance use disorders were examined in a cohort of 325 recently hospitalized psychiatric patients (53% schizophrenia or schizoaffective disorder). Alcohol use was the most common type of substance use disorder, followed by cannabis and cocaine use. Univariate analyses indicated that gender (male), age (younger), education (less), history of time in jail, conduct disorder symptoms, and antisocial personality disorder symptoms were predictive of substance use disorders. Lifetime cannabis use disorder was uniquely predicted by marital status (never married) and fewer psychiatric hospitalizations during the previous 6 months. Optimal classification tree analysis, an exploratory, nonlinear method of identifying patient subgroups, was successful in predicting 74 percent to 86 percent of the alcohol, cannabis, and cocaine use disorders. The implications of this method for identifying specific patient subgroups and service needs are discussed.

A clinical and immunologic study to assess risk of TMA-induced lung disease as related to exposure.

The objective of this study was to determine whether there are trimellitic anhydride (TMA) exposure levels that are very unlikely to cause immunologically mediated respiratory disease. A 3-year clinical and immunologic survey study of 286 employees was conducted at a facility that manufactures TMA. Each employee was assigned an exposure classification from 1 (highest) to 5 (lowest). Of the 28 individuals in exposure class 1, 8 (29%) developed disease; of the 57 class 2 employees, 2 (4%) developed disease; of the 79 class 3 employees, 4 (5%) developed disease. Of the 98 class 4 employees and the 24 class 5 employees, none developed disease. Inasmuch as individuals in class 4 and 5 (TMA exposure < 0.002 mg/m3) are at low risk of developing disease due to TMA, it appears that they do not warrant routine inclusion in surveillance studies.

Computers and connectivity in Illinois emergency departments.

UNLABELLED: Although the Internet has been described as "ubiquitous," little is known about the extent to which physicians have access to the Internet while providing clinical care. OBJECTIVE: To assess the extent of Internet connectivity within the clinical area of every ED within the state of Illinois. METHODS: This was a prospective observational study. Each Illinois ED listed in a published directory was called by telephone, and a responsible party was identified to provide information regarding the type and size of the ED, patient demographics, the types of personal computers (PCs) available in the ED (if any), the types of operating systems used, the availability of access to the World Wide Web (Web), and the highest speed at which an Internet connection could be established. Responses regarding the presence and types of PCs and the types of operating systems used were assessed using one-factor chi-square. Univariate and multivariate predictors of the type of PC used, the presence or absence of Web access, and the highest speed of Internet access were evaluated using optimal discriminant analysis and nonlinear classification tree analysis, respectively. RESULTS: One hundred ninety-eight of the 199 EDs in the state of Illinois (99.5%) completed the survey. Of the responding EDs, 50.5% had PCs, but only 17.6% had Web access. When Web access was available, it was most often available through a high-speed Internet connection that was faster than a dial-up modem. Most departments (68.1%) with PCs used the Windows 95 or Windows 98 operating systems. A majority (62.5%) used the Netscape browser exclusively. Larger EDs (more than six ED beds) in rural or suburban areas were more likely to have a PC compared with smaller EDs (six or fewer beds). Large EDs (more than 12 ED beds) in private tertiary care or academic hospitals were most likely to have Web access. CONCLUSIONS: Although half of Illinois EDs have PCs, only one in six has access to the Internet; thus, most emergency physicians do not have ready access to the Web from the site where they deliver clinical care.

Comparing three preprocessing strategies for longitudinal data. An example in functional outcomes research.

Longitudinal monitoring of individual patient data is becoming routine in physician office practice. This study compares three different methods for evaluating clinical outcomes for individual patients: raw change score analysis versus normative and ipsative statistical analyses. Two discrete samples of intermittent claudication patients making vascular surgery office visits--drawn from interventional management versus stable, routinely followed control groups--were tested four times using both generic and disease-specific functional status measures. Results indicated that the ipsative method was most consistent with several different types of a priori hypotheses that are often evaluated in analysis of repeated measures data.

Screening for undetected mental disorders in high utilizers of primary care services.

OBJECTIVE: To define the prevalence and detection rates of mental disorders among high utilizers as compared with typical utilizers, and to examine the effect of case-mix adjustment on these parameters. DESIGN: Cross-sectional study. SETTING: General internal medicine outpatient clinic associated with an urban, academic medical center. PATIENTS: From patients attending a general medicine clinic, 304 were selected randomly in three utilization groups, defined by number of clinic visits: (1) high utilizers; (2) case-mix adjusted high utilizers; and (3) typical utilizers (control patients). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The presence of any mental disorder was ascertained by the PRIME-MD screening instrument. Chart review on all patients was performed to ascertain mental disorders detected by primary care physicians. The prevalence of mood disorders was markedly higher in high utilizers (29%) than in adjusted high utilizers (15%) or controls (10%) (p <.001). Anxiety disorders were slightly, but not statistically, more prevalent in the group adjusted for case mix (16%) than in other high utilizers (12%) or controls (9%). Alcoholism was significantly more prevalent in controls (12%) than in adjusted (6%) or other high utilizers (3%) (p <.03). The discrepancy in detection rates between PRIME-MD and chart review for any mental disorder was less for high utilizers (37% vs 31%) as compared with adjusted high utilizers (31% vs 11%) or controls (24% vs 8%). CONCLUSIONS: Mood disorders are associated with a high overall burden of illness, while anxiety disorders are more predominant among outliers after case-mix adjustment. Detection rates differ substantially by utilization pattern. Screening efforts can be more appropriately targeted with knowledge of these patterns.

An attempted prospective testing of an asthma severity index and a quality of life survey for 1 year in ambulatory patients with asthma.

It has been recommended that allergist-immunologists use quality of life (QOL) surveys to document their "added value" in patient care. There are little cross-sectional or prospective data regarding longer term follow-up of patients using QOL assessments and none associated with prospective use of an asthma severity index (ASI). Our objective was to identify clinical and psychological correlates of adverse asthma outcomes as assessed using the ASI survey. A 12 item QOL and a nine item ASI survey, spirometry, and history and physical were obtained from patients initially and then every 3 months for a year. The ASI was calculated as follows: one point for each emergency treatment of asthma if not in status asthmaticus, three points for each hospitalization for status asthmaticus, and six points for each intensive care admission or intubation. Patients were 56 adults between ages 18 and 45 with asthma enrolled between May 1994 and February 1996 with the intention to be reassessed quarterly for a year. At enrollment the 56 patients had ASI scores for the previous 12 months ranging from zero to 30. The patient with an ASI of 30 did not return after the initial visit. Of the 13 patients who completed the study, 12 patients had a zero ASI score over a 12-month period; one patient who had an initial score of 26 finished with a score of one. There were no deaths throughout the follow-up period. Of the 43 patients who did not complete the study only six (13.9%) cited local managed care or primary care physician as taking over their care. Initial ASI scores were dichotomized (zero versus greater-than-zero) due to skewness. The forced expiratory volume in one second (FEV1), % predicted FEV1 and peak flow were not related significantly to the dichotomized ASI score. The strongest univariate predictor was the self-assessment of asthma burden using a 78 mm visual analog scale. A two variable model included a query about bodily pain in the last 4 weeks and a self-assessment of general health. The dropout rate was high but only 13.9% of such patients reported that managed care or primary care physicians were responsible. A two variable model was a strong predictor of asthma severity. The single best predictor of asthma severity was a visual analog scale based on the question "How do you think your asthma is?"