Literacy, comprehension, and informed consent in clinical research.

Institutional review boards (IRBs) and informed consent have recently come under increasing scrutiny. The provision of appropriate and understandable information and its comprehension are key elements of the informed consent process. This article examines how literacy and other factors might impact on comprehension of the information provided. Better understanding of these issues and how to best address them are crucial to allowing clinical research subjects to participate as well-informed and willing partners in scientific inquiry.

A new cancer education mission: managed care and clinical trials.

BACKGROUND: The traditional support for clinical research, teaching, and indigent patient care is being seriously compromised by the growth of managed care in the United States. Educational initiatives are needed to ensure the incorporation of clinical trials into the optimal care of cancer patients. METHODS: The Cancer Clinical Trials Task Force of Colorado was established in 1995 to find a collaborative and non-legislative solution to the uncertainty of coverage by third-party payers for cancer patients participating in clinical trials. RESULTS: This program has served to heighten the awareness of the crucial role of clinical trials in defining new treatment strategies among third-party payers. CONCLUSIONS: The Task Force and similar regional and national efforts have begun to provide needed information and education about the importance of clinical trials to the managed care industry; however, much remains to be done to ensure access to and coverage for clinical trials.

Perception of preventive health needs in a prostate-cancer screening population: a preliminary report.

In follow-up of a screening program for prostate cancer, 192 men from the urban Denver area and 244 men from rural northeastern Colorado completed a mailed questionnaire addressing their health and medical care, insurance coverage, lifestyles, and desire for health education and screening programs. Rural respondents were older and more were self-insured. Twice as many urban men were prompted to participate in the prostate screening program by media announcements (51.0% vs 23.4%), while spouses (21.3% vs 9.4%) and physicians (13.1% vs 6.8%) played greater roles in motivating rural participants. The primary topics for health information and education needs perceived by the rural men were cancer-related, while those for urban men concentrated on cardiac risk factors. Both preferred that this information be provided in the form of written materials or through their personal physicians. This pilot study suggests certain differences in the present health practices, motivational factors, and health information and education needs in urban versus rural men. These differences should be explored further and be considered in the design of cancer prevention and screening programs for these populations.

Psychological symptoms and disease-free and overall survival in women with stage II breast cancer. Cancer and Leukemia Group B.

BACKGROUND: The possible link between psychological factors and length of cancer survival has generated a literature of contradictory findings. Associations usually have not been found when general psychological symptoms are assessed. Associations usually have been found for predictors related to expressive versus repressive emotional coping (e.g., depression, "fighting spirit," hostility, and type C personality); however, even these associations have been relatively small, when compared with those for medical factors. Yet few studies have adequately controlled for medical and treatment-related factors. PURPOSE: Within a Cancer and Leukemia Group B (CALGB) national clinical trial of four adjuvant therapy regimens for stage II breast cancer (CALGB 8082), this study prospectively examined the contribution of potential psychological predictors to length of disease-free and overall survival over a 15-year period. METHODS: Subjects were 280 women with stage II breast cancer, out of a total of 899, who were randomly assigned to receive CMFVP (cyclophosphamide-methotrexate-fluorouracil-vincristine-prednisone) for two 6-week cycles or six 4-week cycles, then subsequently randomly assigned to receive or not to receive VATH (vinblastine-doxorubicin-thiotepa-fluoxymesterone). Subjects were recruited during the period between October 1980 and August 1984, inclusive, and followed until January 1996. Prior to chemotherapy, psychological symptoms were assessed using the Symptom Check List-90-Revised (SCL-90-R). SCL-90-R scores were trichotomized into categories representing high, medium, and low distress. Basic base-line sociodemographic data (including age, ethnicity, education, and marital status) and medical data (including lymph node status, estrogen receptor status, menopausal status, and performance status) were collected. Subjects with psychosocial data differed from those without psychosocial data solely in their higher percentage of classification in the mild limitation category of the Zubrod (Eastern Cooperative Oncology Group) performance status rating (subjects with psychosocial data: 14%; subjects without psychosocial data: 8%). RESULTS: In stepwise Cox regression analyses that controlled for sociodemographic and medical variables, there was no significant predictive effect of the level of distress (as measured by the SCL-90-R trichotomized scores) on length of disease-free and overall survival of the study subjects. Risk ratios for low versus high distress were 1.01 (95% confidence interval [CI] = 0.62-1.66) for disease-free survival and 1.03 (95% CI = 0.58-1.82) for overall survival. CONCLUSIONS: This study failed to provide evidence that psychological factors contributed to length of disease-free or overall survival of women who received adjuvant chemotherapy (either CMFVP alone or CMFVP followed by VATH) for treatment of stage II breast cancer. IMPLICATIONS: In the context of far more potent medical factors, the contribution of psychological factors to disease-free and overall survival is likely to be relatively small. Future research should focus on specific theory-driven predictors rather than on general psychological symptoms. Moreover, it should be based on clinical studies using a controlled, prospective design, in which the effects of medical factors may be distinguished and psychological predictors are clear antecedents of survival outcomes.

The treatment of older adult patients with acute myeloid leukemia by triple infusion chemotherapy.

Adult patients (> or = 56 years old) with acute myeloid leukemia (AML) received induction therapy consisting of daunorubicin (60 mg/m2), etoposide (80 mg/m2), and cytarabine (200 mg/m2) daily for 5 days by continuous i.v. infusion (120 hours). The initial protocol was modified so that patients who were not hypoplastic after the first cycle of chemotherapy received a second cycle of treatment, utilizing 30 mg/m2 of daunorubicin/24 hours for 5 days plus etoposide and cytarabine as used in the first cycle. Two courses of consolidation with etoposide and cytarabine at the same dose and schedule were given. Patients were then maintained on cytarabine monthly. Twelve of 29 previously untreated patients (41%) achieved complete remission (CR). Excluding patients with secondary AML, 48% of all patients (11/23) achieved CR, including 56% > or = 70 years old. The median duration of CR was 41 weeks and median survival of CR patients was 54 weeks. Six of 13 patients (46%) with relapsed AML achieved CR. Toxicity in these older adult patients has been mild. Two patients (8%) had severe mucositis and one had severe (bloody) diarrhea. Most patients developed a mild transient asymptomatic rash. Triple infusion chemotherapy (TIC) may be as effective as other chemotherapy regimens for AML in older adults and has acceptable toxicity.

Method for study of endothelium-dependent vasodilatation in rabbit intrarenal arterial network.

The objectives of this study were twofold: 1) to determine whether a microdissected rabbit intrarenal arterial network (IAN), consisting mainly of interlobar, arcuate, and interlobular arteries exhibits endothelium-dependent vasodilatation, and 2) to establish a means of selectively abolishing this response. The IAN was perfused at a constant flow with heated-oxygenated Krebs-bicarbonate buffer through the main renal artery, and evoked responses were limited to vessels distal to the renal artery. A decrease in perfusion pressure reflected a vasodilator response, after vascular tone had been induced by intraarterial infusion of phenylephrine. Bolus injections of acetylcholine produced graded endothelium-dependent vasodilator responses, whereas glyceryl trinitrate caused endothelium-independent responses. Manual de-endothelialization was accomplished by gently stroking the IAN and at the same time removing any remaining glomeruli. This procedure blocked the response to acetylcholine, but not to glyceryl trinitrate (n = 6). A 10-min infusion of NG nitro-L-arginine (NArg) (4 x 10(-5)-3 x 10(-4) M) into the IAN also selectively attenuated the response to acetylcholine (n = 7). The third procedure, consisting of a 10-min infusion of 22-44 mM hydrogen peroxide into the IAN also attenuated the response to acetylcholine, but not to glyceryl trinitrate in nine of 12 experiments. This investigation demonstrates that intrarenal arteries are capable of undergoing endothelium-dependent vasodilatation, and the potential use of the IAN for further study of renal endothelium-derived vasoactive factors.

Renal hemodynamics in canine DOCA-salt hypertension: effect of calcium channel blockade.

Systemic arterial blood pressure (BP), renal blood flow (RBF), and renal vascular resistance (RVR) were followed for 3-4 wks during the progression of DOCA-salt hypertension in the conscious dog. Accompanying the gradual increase in BP was an increase in RBF; however, RVR was unchanged. The hypertension was totally reversed 5-7 days after cessation of DOCA-salt treatment, but the increase in RBF persisted, presumably as a result of renal hypertrophy. Renal adrenoceptor blockade with prazosin (6 dogs) and prazosin plus idazoxan (4 dogs) caused a comparable decrease in BP in the normotensive and DOCA-salt hypertensive dog; however, RVR was decreased only in the normotensive. Similar results were obtained during ganglionic blockade with hexamethonium. The i.v. infusion of diltiazem for 1 wk restored BP of the hypertensive dog to a normotensive level, and hexamethonium given i.v. had little further effect on either BP or RVR. These results suggest a non-neurogenically mediated mechanism of canine DOCA-salt hypertension that is susceptible to calcium channel blockade.

IL-2/LAK cell treatment for advanced cancers with emphasis on a novel administration.

Interleukin-2 (IL-2) is a substance produced by activated blood cells called helper T-lymphocytes and has been shown to stimulate the body's immune system. IL-2 may cause certain tumors to regress when administered intravenously to laboratory animals and humans. Lymphokine activated killer (LAK) cells are white blood cells that have been stimulated with IL-2 in vitro. LAK cells are capable of killing tumor cells both in vitro and in vivo, especially when given along with IL-2. Although this form of treatment has been found to be effective in patients with certain cancers who no longer benefit from standard forms of therapy, the anti-cancer effects of IL-2/LAK cell treatment are limited by the serious, life-threatening side effects of high-dose intravenous administration, and by the high cost. A treatment program with low-dose, intralymphatically-administered LAK/IL-2 in patients with advanced cancer is a promising alternative which circumvents these major problems and concerns, while maintaining high response rates.

Malignant melanoma.

The yearly number of patients with malignant melanoma presenting in the United States is increasing at an alarming rate. Unprotected sun exposure appears to be a major cause for this rise, and appropriate protection will hopefully reverse this worrisome trend.

Bradykinin contribution to renal blood flow effect of angiotensin converting enzyme inhibitor in the conscious sodium-restricted dog.

We examined the relative contribution of renin-angiotensin system blockade and bradykinin potentiation to the renal hemodynamic effect of the angiotensin converting enzyme inhibitor enalaprilat in sodium-deprived dogs. Six conscious dogs instrumented for monitoring of blood pressure (BP) and renal blood flow (RBF) were employed in five groups of experiments. In group 1, enalaprilat alone was administered, and it decreased BP by -24 +/- 3 mm Hg and increased RBF by 135 +/- 15 ml/min. During a constant intravenous infusion of saralasin (group 2), enalaprilat decreased BP by -7 +/- 3 mm Hg and increased RBF by 84 +/- 7 ml/min (delta BP and delta RBF, p less than 0.01 vs. group 1 by analysis of variance). During a constant intrarenal arterial infusion of saralasin (group 3), the respective changes in BP and RBF after enalaprilat were -10 +/- 3 mm Hg and 69 +/- 12 ml/min, and these results did not differ from those of group 2. The infusion of saralasin intravenously or intrarenal arterially decreased BP slightly and increased RBF. In the presence of an intravenous infusion of a specific bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg.TFA (B5630) (group 4), enalaprilat decreased BP by -28 +/- 4 mm Hg and increased RBF by 82 +/- 24 ml/min (delta RBF, p less than 0.01 vs. group 1).(ABSTRACT TRUNCATED AT 250 WORDS)

Resistance to blockade by saralasin of effect of ACE inhibitors in conscious sodium-restricted dog.

Comparison of the effect of captopril and enalaprilat was made on mean systemic arterial blood pressure (BP), renal blood flow (RBF), and renal vascular resistance (RVR) of conscious sodium-replete and sodium-restricted dogs (plasma renin activity = 6.66 ng angiotensin I.ml-1.h-1). BP was decreased by -8 +/- 2 mmHg and RBF was increased by 34 +/- 12 ml/min with captopril given intravenously and by -5 +/- 2 mmHg and 28 +/- 7 ml/min with enalaprilat in sodium-replete dogs. The respective changes in BP and RBF in sodium-restricted dogs were -29 +/- 2 mmHg and 62 +/- 12 ml/min with captopril and -25 +/- 6 mmHg and 53 +/- 18 ml/min with enalaprilat. Saralasin infused intra-arterially to the kidney significantly blocked the increase in RBF seen after angiotensin-converting enzyme (ACE) inhibition in sodium-replete dogs, and reduced the increase in RBF in sodium-restricted dogs, but the latter effect was not statistically significant. A more moderate increase in plasma renin activity was established in another group of sodium-restricted dogs, and saralasin was administered intravenously instead of intra-arterially. Enalaprilat increased RBF in these dogs in the presence of a saralasin blockade (42 +/- 7 ml/min), and this effect was not significantly changed by prior administration of indomethacin (28 +/- 6 ml/min). The results suggest that blockade of the influence of the renin-angiotensin system and possibly another vasodilator mechanism, such as kinin potentiation, account for the increase in RBF after ACE inhibition in the low-sodium state.

Renal hemodynamic effects of a selected calcium antagonist.

Calcium antagonists are unique antihypertensive drugs that appear to exert selective blood pressure-lowering and possibly renal hemodynamic and functional effects in hypertensive patients and animals. There is evidence for inhibition of tubular sodium reabsorption and renal vasodilatation when certain of these agents are given by acute intravenous or intrarenal arterial administration. These renal effects have been observed to occur either independently or together. Both natriuresis and diuresis have been found to occur with these drugs. In the deoxycorticosterone-salt hypertensive dog, chronically administered diltiazem reduces blood pressure, transiently increases renal blood flow and increases urine volume. Administered either acutely or chronically to these hypertensive dogs, diltiazem depresses renal vascular reactivity. Pressor and renal vasoconstrictor responses to angiotensin II and norepinephrine are attenuated to a similar degree. The chronic blood pressure-lowering effect of diltiazem is most likely a function of depressed vascular reactivity; however, actions at other sites cannot be ruled out based on our experiments. Postprandial renal vasodilatation readily occurs in the conscious instrumented dog, and although this response is blocked by the acute administration of a calcium antagonist, the response is unaltered during the chronic administration of diltiazem.

Renal hemodynamics and vascular reactivity in canine DOCA-salt hypertension.

Because of the potential role that the kidney may play in deoxycorticosterone acetate (DOCA)-salt hypertension, changes in renal blood flow, renal vascular reactivity, and renal adrenergic vascular tone were followed in the conscious instrumented dog. DOCA-salt was administered daily after obtaining control measurements. Systemic mean arterial blood pressure (MAP) was monitored with an indwelling catheter, renal blood flow (RBF) was measured electromagnetically using an implanted blood flow probe, and drugs were administered intrarenal arterially through an indwelling renal artery catheter. During the first week of DOCA-salt administration MAP increased from 106 +/- 3 to 118 +/- 2 mmHg and at week 2 to 123 +/- 2 mmHg (P less than 0.01). RBF increased from 275 +/- 32 to 336 +/- 34 during week 1 (P less than 0.05) and to 324 +/- 29 ml/min during week 2. The log ED50 of norepinephrine administered intra-arterially decreased from 1.66 +/- 0.114 to 1.48 +/- 0.091 and 1.41 +/- 0.067 ng/ml (P less than 0.05), and of angiotensin II from 2.58 +/- 0.072 to 2.31 +/- 0.09 (P less than 0.05) and 2.38 +/- 0.05 pg/ml, during weeks 1 and 2, respectively. There was, however, no increase in adrenergic vascular tone as determined by the change in RBF obtained with the intra-arterial infusion of alpha-adrenoceptor antagonists. These experiments indicate that RBF is not compromised in canine DOCA-salt hypertension, and renal adrenergic tone is no greater in the hypertensive than in the normotensive control period.

Antihypertensive and renal vasodilator effect of diltiazem in DOCA-salt hypertensive dog.

We studied the effect of an intravenous (i.v.) infusion of diltiazem (15 micrograms/kg/min) given for 1 week on several cardiovascular parameters, renal blood flow, and electrolyte and urinary excretion in chronically instrumented DOCA-salt hypertensive dogs. On the first recording session, 24 h after diltiazem infusion was started, arterial blood pressure was decreased and renal blood flow was increased by 36%. Thereafter, the blood pressure reached a normotensive level and remained at that level for the duration of the infusion in all but one dog in which the dose had to be increased on day 7. Renal blood flow was increased for 3 days and then tended to return toward control at the end of the infusion period. An increase in urine output was seen during the period of drug infusion, but no increase in sodium excretion was detected. Pressor and renal blood flow responses to norepinephrine (NE), phenylephrine, and angiotensin II were evoked before and on the last day of the diltiazem infusion. The decreases in renal blood flow produced by all three agonists and the pressor response to NE were reduced by diltiazem. These results indicate that this calcium entry blocker can reestablish blood pressure to a normotensive level in DOCA-salt--treated dogs, but that the renal vasodilator effect accompanying the blood pressure decrease is not consistently sustained.

Chemotherapy for breast cancer decreases plasma protein C and protein S.

An increased incidence of thromboembolic events has been described in women receiving chemotherapy for breast cancer. The etiology of this enhanced thrombotic state has not been defined. We performed serial coagulation studies in 15 women during 1 monthly cycle of cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for breast cancer; seven adjuvant and eight metastatic. Plasma protein C levels were measured by anticoagulant, amidolytic, and antigenic techniques. Antigen levels of both total and free plasma protein S were quantitated by immunoelectrophoresis. Plasma levels of protein C, an important vitamin K-dependent inhibitor of blood coagulation and a profibrinolytic agent, and protein S, a cofactor for protein C, decreased 1 and 2 weeks after initiation of chemotherapy compared with pretreatment values. Plasma levels of factor VII and fibrinogen also decreased. The changes in protein C and protein S may contribute to the enhanced thrombotic tendency described in this setting. Possible mechanisms for the decreases in plasma protein C, protein S, factor VII, and fibrinogen are discussed.

Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081.

In a prospective, randomized trial Cancer and Leukemia Group B (CALGB) evaluated CAF chemotherapy (cyclophosphamide + doxorubicin + 5-fluorouracil [5-FU]) v CAF plus tamoxifen (TCAF) in advanced breast cancer. Patients were stratified by estrogen receptor (ER) status, dominant site of metastatic disease, menopausal status, and prior adjuvant therapy. Regardless of ER status or menopausal status, the addition of tamoxifen conferred no significant advantage in response rate, response duration, time to treatment failure (TTF) or survival over CAF alone. A secondary objective was to compare the response to CAF of ER positive (ER+) and ER negative (ER-) patients to determine if there was a differential response to cytotoxic chemotherapy. Response rates of ER+ and ER- patients to CAF were identical (56%), but the response duration, time to treatment failure, and survival of ER+ patients were significantly longer than ER- patients. This lack of differential response implies that chemotherapy and hormonal therapy may compete for the same pool of ER+ cells. It also suggests that chemotherapy kills breast cancer cells indiscriminately, regardless of ER status.

Platelet dysfunction in acute megakaryoblastic leukemia.

Acute megakaryoblastic leukemia occurred in an adolescent. There was considerable bleeding despite only moderate thrombocytopenia, and both platelet structure and platelet function were abnormal. To our knowledge, platelet dysfunction has only once been documented in this acute leukemia, although in other leukemias with megakaryocytic predominance, notable bleeding has been observed in the absence of thrombocytopenia.