Informed consent for clinical trials: a comparative study of standard versus simplified forms.

BACKGROUND: A high level of reading skill and comprehension is necessary to understand and complete most consent forms that are required for participation in clinical research studies. This study was conducted to test the hypothesis that a simplified consent form would be less intimidating and more easily understood by individuals with low-to-marginal reading skills. METHODS: During July 1996, 183 adults (53 patients with cancer or another medical condition and 130 apparently healthy participants) were tested for reading ability and then asked to read either the standard Southwestern Oncology Group (SWOG) consent form (16th grade level) or a simplified form (7th grade level) developed at Louisiana State University Medical Center-Shreveport (LSU). Participants were interviewed to assess their attitudes toward and comprehension of the form read. Then they were given the alternate consent form and asked which one they preferred and why. RESULTS: Overall, participants preferred the LSU form (62%; 95% confidence interval [CI] = 54.8%-69.2%) over the SWOG form (38%; 95% CI = 30.8%-45.2%) (P = .0033). Nearly all participants thought that the LSU form was easier to read (97%; 95% CI = 93.1%-99.9%) than the SWOG form (75%; 95% CI = 65.1%-85.7%) (P<.0001). However, the degree to which the participants understood the forms was essentially the same for the LSU form (58%; 95% CI = 48.6%-67.0%) and the SWOG form (56%; 95% CI = 43.8%-66.8%). IMPLICATIONS: These findings raise serious questions regarding the adequacy of the design of written informed consent documents for the substantial proportion of Americans with low-to-marginal literacy skills.

Expression of cadherin-6 as a novel diagnostic tool to predict prognosis of patients with E-cadherin-absent renal cell carcinoma.

In many carcinomas, E-cadherin is considered to be a prognostic marker for patient survivals, and its decreased expression is associated with metastatic disease. Among renal cell carcinomas (RCCs), however, only 20% of tumors express E-cadherin, whereas a much higher percentage express other cadherins, e.g., N-cadherin and cadherin-6 (T. Shimazui et al, Cancer Res., 56: 3234-3237, 1996). Among these cadherins expressed in RCCs, cadherin-6 has been identified as a major cadherin in the renal proximal tubules and in the tumors themselves. Hence, we have investigated the relationship between prognosis and cadherin-6 expression in tumor cells in 43 patients with RCC. Expression of cadherin-6, E-cadherin, and alpha-catenin was detected immunohistochemically and evaluated microscopically as normal, heterogeneous, or absent. Normal, heterogeneous, and absent expression of cadherin-6 were observed in 19, 16, and 8 of 43 cases, respectively. Coexpression of E-cadherin and cadherin-6 was detected in only 10 cases. Among 30 tumors in which E-cadherin expression was absent, 24 expressed cadherin-6. In addition, the expression pattern of alpha-catenin correlated more highly with that of cadherin-6 than it did with E-cadherin (P = 0.0003 versus 0.025). In survival analyses, aberrant expression of cadherin-6 correlated with poor survivals both among all patients (P = 0.0009) and in those with E-cadherin-absent RCC (P = 0.0008). These results suggest that cadherin-6 is a major cadherin playing an essential role in cell-cell adhesion in E-cadherin-absent RCC.

Expression of the translation initiation factor eIF4E in the polyp-cancer sequence in the colon.

The eukaryotic translation initiation factor 4E (eIF4E) has been shown to play a key role in cell growth, and several studies have documented an increased expression of eIF4E in a number of solid tumors, including breast, bladder, cervical, and head and neck cancers. This study was done to evaluate the potential role of eIF4E in the polyp-cancer sequence in the colorectum. Eighty-seven cases with lesions in the colorectum with a variety of histopathological diagnoses were randomly selected from the archives of the Pathology Department at Louisiana State University Health Sciences Center-Shreveport. Appropriate sections were selected for immunostaining with eIF4E. The medical records of the patients were reviewed, and demographic information was collected. All statistical analyses were performed using SAS software. A statistically significant relationship was found between the level of eIF4E expression and histological type of lesion: the lowest level of eIF4E expression was found in normal colon tissue, whereas the highest level of eIF4E expression was found in colorectal adenocarcinomas. Carcinomatous lesions were found to have a 43 times higher chance of having a high level of eIF4E expression compared with normal tissue (95% confidence interval, 8.0-213.6, P < 0.0001). In a multivariate analysis, histological type was the only variable that showed a significant relationship with eIF4E expression; no effect was found due to age, gender, race, history of polyps, and family history. The results from this study are consistent with other data from the literature and support the suggestion that eIF4E is strongly involved in colon tumorigenesis. eIF4E might be a useful intermediate biomarker for use in chemoprevention intervention studies in patients with colorectal polyps.

Multiple endocrine neoplasia syndrome type 2: the value of screening and central registration. A study of 15 kindreds in The Netherlands.

Since 1975, 10 families with the multiple endocrine neoplasia (MEN)-2A syndrome and five with the MEN-2B syndrome, making a total of 101 patients, have been identified in The Netherlands. Twenty-three of the MEN-2A patients died before the start of the screening program. The average age of the patients whose death was due to pheochromocytoma (n = 11) or medullary thyroid carcinoma (n = 12) was 34.9 and 49.2 years, respectively. Eighty-seven patients with the MEN-2A syndrome and eight with the MEN-2B syndrome underwent thyroidectomy for C-cell hyperplasia and/or medullary thyroid carcinoma. Eighteen patients had signs or symptoms caused by MEN-2A (group A), 60 were relatives of these patients who had been found to be affected at the first screening of the family (group B), and nine relatives had had negative screening results that later became positive (group C). Five patients had signs or symptoms due to MEN-2B (group A) and three were relatives of these patients who had been found to be affected at the initial screening (group B). To assess the effect of screening, we compared these groups with respect to the occurrence of metastatic medullary thyroid carcinoma at thyroidectomy and the results of the postoperative calcitonin tests. Among the MEN-2A families, 72 percent of group A, 33 percent of group B, and none of group C were found to have metastatic medullary thyroid carcinoma at surgery. In the MEN-2B families, all five patients in group A and one of the three patients in group B had metastatic disease. The "cure rates" in these three groups with MEN-2A, as determined by stimulated calcitonin assessment, were 11, 57, and 100 percent, respectively. One of the five patients with MEN-2B in group A and two of the three patients in group B showed normalization of the stimulated calcitonin value after surgery. From these results, it may be concluded that screening can lead to the detection of medullary thyroid carcinoma in an earlier stage, which in turn may permit curative treatment and improvement of both prognosis and life expectancy. The need for supervision of affected families by central registration to promote periodic examination and to guarantee the continuity of such screening is discussed.

Early prediction of prognosis in out-of-hospital cardiac arrest.

Of 347 victims of out-of-hospital cardiac arrest 196 (56.5%) died before and 109 (31.4%) after admission to hospital, while 42 patients (12.1%) were discharged alive. The 37 patients (10.7%) discharged without severe hypoxic brain damage were assigned to the group with "good", the remaining 310 patients to the group with "poor outcome". From results of stepwise logistic regression, a score was derived to specifically identify victims with poor prognosis (values in brackets = score points; cutpoint: score greater than 3 points): age less than or equal to 70 (0), 71-80 (1), greater than 80 (2); ECG ventricular fibrillation (0), other (1); no aspiration (0), aspiration (1); pupils round (0), not round (1); gasping (0), apnea (1); bystander resuscitation--yes (0), no (1). Evaluation of the score revealed a specificity of 100% (0.95 confidence interval: 80%-100%) and predictive value of 100% (0.95 confidence interval: 95%-100%). A predictive score for specific identification of victims with poor prognosis can contribute to decision making in out-of-hospital cardiac arrest.

Single-dose pharmacokinetics of bupropion in adolescents: effects of smoking status and gender.

Sustained-release (SR) bupropion (Zyban) is approved as a smoking cessation aid for adults. Since smoking often begins in adolescence, we determined the single-dose pharmacokinetics of bupropion SR in 75 adolescent subjects ranging from 13 to 18 years old. Subjects self-reported their smoking status. Urinary cotinine concentration was used to verify smoking status. Thirty-seven subjects (18 males, 19 females) were classified as cigarette smokers and 38 were nonsmokers (19 males, 19 females). Fasted subjects received one tablet (150 mg) of bupropion SR, and plasma samples were collected before (0) and 1/2, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours after dosing. Plasma samples were analyzed for bupropion and its three major metabolites (hydroxybupropion and the aminoalcohol isomers, erythrohydrobupropion plus threohydrobupropion, expressed as a composite) by solid-phase extraction, followed by LC/MS/MS. Factorial analysis of variance (ANOVA) was used to evaluate the effects of smoking and gender on pharmacokinetic parameters. Smokers and nonsmokers differed significantly (p < 0.05) in age and urinary cotinine (p < 0.01) concentration but did not differ significantly in mean weight, height, body surface area, or body mass index. The pharmacokinetic (PK) parameters for bupropion and hydroxybupropion did not differ between smokers and nonsmokers, but differences were found between male and female subjects. Mean values for area under the plasma concentration versus time curve (AUC0-->infinity), volume of distribution (Vd beta) normalized to body weight, maximum plasma concentration (Cmax), and elimination half-life (t1/2 beta) for bupropion were significantly (p < 0.05) greater in females than males, while clearance of bupropion normalized to body weight (CL/f) did not differ between males and females. Females also exhibited significantly (p < 0.05) larger values for hydroxybupropion mean AUC0-->infinity and Cmax than males. The mean ratio of hydroxybupropion to bupropion AUC for adolescents was approximately 4 to 5, which is lower than that previously reported for adults. In conclusion, smoking status does not affect the single-dose pharmacokinetics of bupropion SR in adolescents. However, females differ from males in several potentially important PK parameters for bupropion and its major metabolite, hydroxybupropion.

Tobacco use among male high school athletes.

PURPOSE: The purpose of this study was to compare tobacco use among high school male athletes with their nonathlete counterparts. We hypothesized that there was an inverse correlation between the intensity level of the sport and frequency of tobacco use. METHODS: Students were surveyed at seven high schools in northwest Louisiana using a 109-item questionnaire. Of the 1,200 males tested, 83% participated in one or more sports. The mean age was 15.8, and mean grade level was 10th. Sixty-seven percent were white, 27% African-American (AA), and 6% other. RESULTS: Forty-one percent of the adolescent males tested were one or more tobacco products, 31% reported cigarette smoking, 21% chewed tobacco, and 18% used snuff. Eleven percent reported using all three tobacco products. Race was a significant determinant of tobacco use, with whites being more likely to use each of the three tobacco products (P < .001). Medium- and high-intensity athletes were significantly (P < .01) less likely to be heavy smokers than athletes participating in low-intensity sports and nonathletes. However, athletes of each intensity sport used chewing tobacco and snuff at significantly higher rates (P < .001) than nonathletes. When race and grade point average were controlled, sports intensity was a significant predictor of smokeless tobacco use but not overall smoking behavior. Both AA and white high school male athletes at all sport intensity levels were using chewing tobacco and snuff at a rate higher at least 1.5 times that of their nonathlete counterparts. CONCLUSIONS: In our study, high school males' sports participation was a predictor of smokeless tobacco use but not overall smoking behavior. Although the probability of AA high school athletes using smokeless tobacco was low compared to whites, the pattern of use was similar across intensity levels of sports.

Breast cancer diagnosis and survival in women with and without breast implants.

The stage at diagnosis and the survival experience of 41 women who developed breast cancer after cosmetic breast augmentation were compared with those of all other patients with breast cancer (n = 13,246) diagnosed in Alberta from 1973 to 1990 (inclusive). The tumors in women with breast implants were smaller (65.9 percent < or = 2 cm) as compared with the tumors in women without implants (34.1 percent < or = 2 cm), but lymph node and distant metastases were equally frequent in the two groups. The distribution of tumor histologic types did not differ significantly between women with or without implants. Women who had an implant were younger at diagnosis of breast cancer compared with women with breast cancer and no breast implants. The relative 5- and 10-year survival rates did not differ significantly between the two groups, and the Kaplan-Meier survival estimate also was similar. It is concluded that women with breast implants in whom breast cancer develops are not diagnosed in a later stage and do not experience an impaired survival as compared with breast cancer patients without implants.

Cancer screening: overview and prospects.

In Table 4, current "state-of-the-art" screening for various cancers is summarized. It is fair to say that, unfortunately, only a minority of the tumors do have proven screening methods that lead to a lower disease-specific mortality. Given the relative lack of improvement in survival rates over the last few decades, this area should be a priority for research endeavors.

Progress against cancer...?!

Data from the population based cancer registry in Alberta, Canada as well as from the National Canadian Cancer registry were used to evaluate the outcome of oncologic treatment over the past 25 years. Age standardized incidence rates for all cancers combined, and for most individual cancer sites separately, show a continuous increase over time. Overall, the mortality rates have been increasing as well. Age specific trends in incidence and mortality show that, despite an increase in incidence rate, only in childhood cancers does a decrease in mortality exist. However, in patients aged 50 years or more at the time of the cancer diagnosis an increase in mortality was noted which actually exceeded the increase in incidence. Site specific analysis showed a decreasing trend in mortality for Hodgkin's disease, testicular cancer, stomach cancer, and melanoma (in females). A disturbingly increasing trend, specifically in women, existed for lung cancer mortality. It is projected that in women in Alberta mortality from lung cancer will surpass breast cancer mortality to become the number one cancer killer in women within the next few years. The overall 1-year, 2-year, and 5-year relative survival for all cancers combined remained constant over the 25-year period covered in this study. In conclusion, when analyzing the three indicators (incidence, mortality, and survival rates) of success in the fight against cancer no objective signs of progress could be found. Exceptions are the childhood cancers and relatively infrequent tumors such as Hodgkin's disease and testicular cancer. A plea is made for a shift in funding towards an increased emphasis on applied prevention programs and research.

Prostate-specific antigen (PSA) in women.

Prostate-specific antigen (PSA) is a valuable tumor marker for prostate cancer. It was believed that PSA was produced exclusively by the epithelial cells of the prostate gland, but a large body of evidence demonstrates that PSA is not a prostate-specific molecule. PSA has been shown to be expressed in many forms of female tissues. The breast is a major female organ able to produce PSA. PSA is detected in both normal and abnormal breast tissues, as well as in various breast fluids including milk, nipple aspirate, and cyst fluid. Androgens and progesterones, via their receptors, regulate the production of PSA in breast tissue. Clinical studies demonstrate that PSA in breast cancer is associated with the expression of estrogen receptor and progesterone receptor. Women with PSA-positive breast cancer have better disease-free survival as well as overall survival than those with PSA-negative breast cancer. PSA levels in nipple aspirate fluid may be indicative of breast cancer risk. High concentrations of PSA are found in amniotic fluid and the levels change with gestational age. Pregnant women have elevated serum PSA. PSA levels in serum also vary during menstrual cycles and increase in women with excess androgen. Clinical implications of PSA in amniotic fluid and female serum have been suggested. More studies are needed to further explore their utilities.

Insulin-like growth factors and cancer.

Insulin-like growth factors (IGFs) regulate important cellular activities involving cell proliferation, differentiation, and apoptosis. Emerging evidence suggests that members of the IGF family, including IGF-1, IGF-2, the IGF-1 receptor (IGF-1R), and the IGF binding proteins (IGFBPs), play important roles in the development and progression of cancer. Both in vitro and in vivo studies show that IGFs are strong mitogens for a variety of cancer cells. IGF-1 also has an antiapoptotic action on cancer. IGF-1R, overexpressed in cancer cells, mediates the effects of IGFs and plays a role in cell transformation induced by tumor virus and oncogene products. IGFBPs inhibit the actions of IGFs and mediate the anti-proliferative effect of wild-type p53 protein, retinoic acid, vitamin D, and transforming growth factor-beta (TGF-beta). Findings from epidemiologic studies support the involvement of IGF in cancer etiology. Diet, nutrition, and other lifestyle features affect the expression and production of IGF-1 and other members of the IGF family. This may provide new approaches for cancer prevention. Growth hormone (GH) stimulates the production of IGF-1. Use of GH replacement therapy to improve physiological and psychological well-being and to prevent aging-related diseases has been recommended. Given the close relationship between GH and IGF-1, the long-term safety of GH treatment warrants a serious concern.

[Resuscitation after intoxication with amitriptylin]. / Fallbericht einer protrahierten Reanimation bei Suizidversuch mit Amitriptylin.

Intoxications with tricyclic antidepressants are often life threatening situations. In consequence of interference with many organ systems specific treatment consists in transportation to hospital under cardiopulmonary monitoring by physicians. The multiple possibilities of complications require the following treatments: continuous monitoring of the cardiovascular system, gastrolavage, application of carbon through a nasogastric tube, intubation and controlled ventilation in case of coma and continuous stand by for defibrillation. Additionally patients with stable parameters should be monitored in intensive care units because often there are no precursors of cardiac or pulmonary complications. We report the case of a 49-year old women with ingestion of 2500 mg of amitriptyline who suffered from multiple cardiac arrhythmias with following cardiac arrests and who required multiple defibrillations and resuscitation.

New concepts in health care: some preliminary ideas.

Health care discussions in many countries tend to focus on cost containment without taking into account the problem of quality of care. The starting point for our ideas is the description of quality as the optimal relation between care demander and care provider. The difficulties in assessing quality of care are outlined. The question remains which health care model offers the best opportunities to have both high quality care and affordable costs. A proposal is made for a model in which the care demander and care provider, i.e. the client and physician, are natural allies. A special role is fulfilled by the family physician: a key role, as case manager, as gatekeeper. Special attention should be directed towards the financial consequences. It is proposed that small-scale experiments should be started to evaluate the model advanced in the text.

Nonsteroidal anti-inflammatory drugs for the prevention of colon cancer.

OBJECTIVE: To summarize the results of animal and human studies of the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on neoplastic growth in the colon and to outline the possible mechanisms involved. DATA SOURCES: Research articles published in English before June 1992 were identified from MEDLINE. STUDY SELECTION: Nine articles on the polyp-cancer sequence were reviewed, 8 on the apparent pathophysiologic aspects of tumour inhibition by NSAIDs and 22 on animal and human research into the effect of NSAIDs on colon carcinogenesis. RESULTS: The results of animal and human research into the anticarcinogenic effect of NSAIDs suggest that the drugs are effective in preventing tumour growth in the colon. CONCLUSIONS: Intervention studies in humans are necessary to elucidate the therapeutic possibilities of NSAIDs, particularly in populations at increased risk for the development of colon cancer.

[Bleomycin-induced pneumonia]. / Bleomycin-induzierte Pneumonitis.

We report on a case of a 38-year old patient with fatal bleomycin-induced pneumonitis. Clinical presentation, the impact of risk factors, therapeutic means and perioperative considerations to prevent this rare but life-threatening complication are reviewed.

[Resuscitation in multiple trauma]. / Reanimation bei Polytrauma.

We report on a case of successful outpatient cardiopulmonary resuscitation of cardiac arrest after blunt multisystem injury. The literature is discussed and prognostic indicators are described.

[First aid and prognosis following drowning accidents. Results of a retrospective study of 115 cases]. / Erstversorgung und Prognose nach Ertrinkungsunfällen. Ergebnisse einer retrospektiven Untersuchung an 115 Fällen.

OBJECTIVE AND STUDY DESIGN: In 115 cases of submersion the initial findings of the rescue team, the patients status in the emergency room and the course of clinical treatment were analyzed retrospectively. RESULTS: Submersion accidents happened preferably in February, March and in the summertime from May to August. Most of the accidents took place in public waters or public baths (85.2%). Children below 10 years of age were involved in 34.8% of the submersion accidents. 57 patients were near drowned and 58 patients were drowned. The prognosis of patients with detectable heartbeat at the site of the accident depends on the primary pulmonary lesion. If respiratory insufficiency is recognized early and treated aggressively by intubation and mechanical ventilation with PEEP, these patients have an excellent prognosis. Only one patient with detectable heartbeat died, typically, after delayed treatment of respiratory failure. 55 patients recovered completely; one patient was suffering from a lesion of the n. medianus. Contrariwise, the prognosis of patients without detectable heartbeat is mainly determined by the consequences of hypoxaemia and is, overall, poor. Though resuscitation succeeds in 50% of submersion victims, only one out of four successfully resuscitated patients survived with little or no neurologic damage. Severe hypothermia may improve the prognosis of submersion victims. CONCLUSION: Thus, there are no useful parameters that would accurately predict the individual course of a submersion victim.

Breast augmentation: a risk factor for breast cancer?

BACKGROUND: A relation between breast augmentation and the subsequent risk of breast cancer has been postulated. Since an estimated 2 million women in the United States alone have received breast implants, even a small increase in the risk of breast cancer could have considerable public health consequences. METHODS: We performed a population-based nonconcurrent cohort-linkage study. All women in Alberta, Canada, who underwent cosmetic breast augmentation from 1973 through 1986 were included in the implant cohort (n = 11,676). This cohort was compared with the cohort of all women in Alberta in whom a first primary breast cancer was diagnosed (n = 13,557). The expected number of breast-cancer cases in the implant cohort was estimated by applying age-specific and calendar year--specific incidence rates of breast cancer (obtained from the Alberta Cancer Registry) to the implant cohort. Standardized incidence ratios were calculated by dividing the observed by the expected number of breast-cancer cases in the implant cohort. RESULTS: Forty-one patients with implants were subsequently found to have breast cancer. The expected number was 86.2. The standardized incidence ratio was thus 47.6 percent, significantly lower than expected (P less than 0.01). The average length of follow-up in the implant cohort was 10.2 years, and the average length of time from breast augmentation to the diagnosis of breast cancer was 7.5 years. CONCLUSIONS: Women who undergo breast augmentation with silicone implants have a lower risk of breast cancer than the general population. This finding suggests that these women are drawn from a population already at low risk and that the implants do not substantially increase the risk.

Insulin-like growth factor-I and prostate cancer: a meta-analysis.

Some, but not all, epidemiological found have shown that high circulating levels of insulin-like growth factor-I (IGF-I) are associated with an increased risk of prostate cancer. We performed a meta-analysis on all the studies reported so far to evaluate this association. In our Medline search, 14 case-control studies were identified. A standard protocol abstracted information for each study. Hedges' standardized mean difference (HSMD) and odds ratio (OR) were used to estimate the effect of IGF-I and IGF-binding proteins (IGFBP-3). The combined data showed that circulating levels of IGF-I were significantly higher in prostate cancer patients (HSMD = 0.194). The OR for prostate cancer was 1.47 (95% confidence interval (CI) 1.23-1.77) among men with high IGF-I compared to those with low IGF-I. The OR was 1.26 (95% CI 1.03-1.54) for IGFBP-3. Circulating levels of IGF-I and IGFBP-3 are likely to be higher in prostate cancer patients than in the controls. These findings support the suggestion that high IGF-I and IGFBP-3 are associated with an increased risk of prostate cancer.