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Background: Whether patient navigation improves outcomes for patients with comorbidities is unknown. The aims of this study were to determine the effect of comorbidities on the time to diagnostic resolution after an abnormal cancer screening test and to examine whether patient navigation improves the timeliness and likelihood of diagnostic resolution for patients with comorbidities in comparison with no navigation., Methods: A secondary analysis of comorbidity data collected by Patient Navigation Research Program sites using the Charlson Comorbidity Index (CCI) was conducted. The participants were 6,349 patients with abnormal breast, cervical, colon, or prostate cancer screening tests between 2007 and 2011. The intervention was patient navigation or usual care. The CCI data were highly skewed across projects and cancer sites, and the CCI scores were categorized as 0 (CCI score of 0 or no comorbidities identified; 76% of cases); 1 (CCI score of 1; 16% of cases), or 2 (CCI score ≥ 2; 8% of cases). Separate adjusted hazard ratios for each site and cancer type were obtained, and then they were pooled with a meta-analysis random effects methodology., Results: Patients with a CCI score ≥ 2 had delayed diagnostic resolution after an abnormal cancer screening test in comparison with those with no comorbidities. Patient navigation reduced delays in diagnostic resolution, with the greatest benefits seen for those with a CCI score ≥ 2., Conclusions: Persons with a CCI score ≥ 2 experienced significant delays in timely diagnostic care in comparison with patients without comorbidities. Patient navigation was effective in reducing delays in diagnostic resolution among those with CCI scores > 1. Cancer 2017;123:312-318. © 2016 American Cancer Society., Competing Interests: Summary: The authors report no conflicts of interest., (© 2016 American Cancer Society.)

Background: Patient navigation was developed to address barriers to timely care and reduce cancer disparities. The current study explored navigation and racial and ethnic differences in time to the diagnostic resolution of a cancer screening abnormality., Methods: The authors conducted an analysis of the multisite Patient Navigation Research Program. Participants with an abnormal cancer screening test were allocated to either navigation or control. The unadjusted median time to resolution was calculated for each racial and ethnic group by navigation and control. Multivariable Cox proportional hazards models were fit, adjusting for sex, age, cancer abnormality type, and health insurance and stratifying by center of care., Results: Among a sample of 7514 participants, 29% were non-Hispanic white, 43% were Hispanic, and 28% were black. In the control group, black individuals were found to have a longer median time to diagnostic resolution (108 days) compared with non-Hispanic white individuals (65 days) or Hispanic individuals (68 days) (P<.0001). In the navigated groups, black individuals had a reduction in the median time to diagnostic resolution (97 days) (P<.0001). In the multivariable models, among controls, black race was found to be associated with an increased delay to diagnostic resolution (hazard ratio, 0.77; 95% confidence interval, 0.69-0.84) compared with non-Hispanic white individuals, which was reduced in the navigated arm (hazard ratio, 0.85; 95% confidence interval, 0.77-0.94)., Conclusions: Patient navigation appears to have the greatest impact among black patients, who had the greatest delays in care. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2715-2722. © 2016 American Cancer Society., Competing Interests: The authors report no conflicts of interest., (© 2016 American Cancer Society.)

Objective: Cancer patients and survivors are assuming active roles in decision-making and digital patient support tools are widely used to facilitate patient engagement. As part of Cancer Information Service Research Consortium's randomized controlled trials focused on the efficacy of eHealth interventions to promote informed treatment decision-making for newly diagnosed prostate and breast cancer patients, and post-treatment breast cancer, we conducted a rigorous process evaluation to examine the actual use of and perceived benefits of two complementary communication channels -- print and eHealth interventions., Methods: The three Virtual Cancer Information Service (V-CIS) interventions were developed through a rigorous developmental process, guided by self-regulatory theory, informed decision-making frameworks, and health communications best practices. Control arm participants received NCI print materials; experimental arm participants received the additional V-CIS patient support tool. Actual usage data from the web-based V-CIS was also obtained and reported., Results: Print materials were highly used by all groups. About 60% of the experimental group reported using the V-CIS. Those who did use the V-CIS rated it highly on improvements in knowledge, patient-provider communication and decision-making., Conclusion: The findings show that how patients actually use eHealth interventions either singularly or within the context of other communication channels is complex., Practice Implications: Integrating rigorous best practices and theoretical foundations is essential and multiple communication approaches should be considered to support patient preferences.

Background: Patient navigation is a promising intervention to address cancer disparities but requires a multisite controlled trial to assess its effectiveness., Methods: The Patient Navigation Research Program compared patient navigation with usual care on time to diagnosis or treatment for participants with breast, cervical, colorectal, or prostate screening abnormalities and/or cancers between 2007 and 2010. Patient navigators developed individualized strategies to address barriers to care, with the focus on preventing delays in care. To assess timeliness of diagnostic resolution, we conducted a meta-analysis of center- and cancer-specific adjusted hazard ratios (aHRs) comparing patient navigation vs usual care. To assess initiation of cancer therapy, we calculated a single aHR, pooling data across all centers and cancer types. We conducted a metaregression to evaluate variability across centers. All statistical tests were two-sided., Results: The 10521 participants with abnormal screening tests and 2105 with a cancer or precancer diagnosis were predominantly from racial/ethnic minority groups (73%) and publically insured (40%) or uninsured (31%). There was no benefit during the first 90 days of care, but a benefit of navigation was seen from 91 to 365 days for both diagnostic resolution (aHR = 1.51; 95% confidence interval [CI] = 1.23 to 1.84; P < .001)) and treatment initiation (aHR = 1.43; 95% CI = 1.10 to 1.86; P < .007). Metaregression revealed that navigation had its greatest benefits within centers with the greatest delays in follow-up under usual care., Conclusions: Patient navigation demonstrated a moderate benefit in improving timely cancer care. These results support adoption of patient navigation in settings that serve populations at risk of being lost to follow-up., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Navigators can facilitate timely access to cancer services, but to the authors' knowledge there are little data available regarding their economic impact., Methods: The authors conducted a cost-consequence analysis of navigation versus usual care among 10,521 individuals with abnormal breast, cervical, colorectal, or prostate cancer screening results who enrolled in the Patient Navigation Research Program study from January 1, 2006 to March 31, 2010. Navigation costs included diagnostic evaluation, patient and staff time, materials, and overhead. Consequences or outcomes were time to diagnostic resolution and probability of resolution. Differences in costs and outcomes were evaluated using multilevel, mixed-effects regression modeling adjusting for age, race/ethnicity, language, marital status, insurance status, cancer, and site clustering., Results: The majority of individuals were members of a minority (70.7%) and uninsured or publically insured (72.7%). Diagnostic resolution was higher for navigation versus usual care at 180 days (56.2% vs 53.8%; P = .008) and 270 days (70.0% vs 68.2%; P < .001). Although there were no differences in the average number of days to resolution between the 2 groups (110 days vs 109 days; P = .63), the probability of ever having diagnostic resolution was higher for the navigation group versus the usual-care group (84.5% vs 79.6%; P < .001). The added cost of navigation versus usual care was $275 per patient (95% confidence interval, $260-$290; P < .001). There was no significant difference in stage distribution among the 12.4% of patients in the navigation group vs 11% of the usual-care patients diagnosed with cancer., Conclusions: Navigation adds costs and modestly increases the probability of diagnostic resolution among patients with abnormal screening test results. Navigation is only likely to be cost-effective if improved resolution translates into an earlier cancer stage at the time of diagnosis., (© 2013 American Cancer Society.)

Purpose: When faced with a significant recruitment challenge for three nationwide psychoeducational trials targeting prostate and breast cancer patients, the Cancer Information Service Research Consortium initiated outreach efforts to increase accrual. Recruitment is reported by major outreach strategy to inform the use of similar campaigns, either as primary recruitment efforts or to supplement "in-reach" recruitment within oncology settings., Methods: During a 33-month period, recruitment was tracked from the National Cancer Institute's Cancer Information Service (CIS), the American Cancer Society (ACS), Dr. Susan Love Research Foundation's Love/Avon Army of Women (AOW), Internet advertising, press releases, radio/television interviews, recruitment materials in community venues, and outreach to churches and cancer support organizations., Results: Across projects, the majority (89 %) of recruited participants (N = 2,134) was obtained from the CIS (n = 901, 19 months of recruitment), AOW (n = 869, 18 months), and ACS (n = 123, 12 months). Other efforts showed minimal gain in recruitment., Conclusions: Cancer information programs (e.g., CIS and ACS) and registries of individuals willing to participate in cancer-related research (e.g., AOW) can represent exceptional resources for outreach recruitment of cancer patients, especially when the eligibility criteria are highly restrictive. However, these resources do not yield samples representative of the larger population of adults diagnosed with cancer, and conclusions from such trials must be tempered accordingly., Implications for Cancer Survivors: Inadequate recruitment to randomized controlled trials limits the creation of useful interventions for cancer survivors. By enrolling in cancer registries and taking part in research, cancer survivors can contribute to the development of effective resources for the survivor population.

The authors describe 3 large randomized trials from the Cancer Information Service Research Consortium. Three web-based multimedia programs are being tested to help newly diagnosed prostate (Project 1) and breast cancer patients (Project 2) make informed treatment decisions and breast cancer patients prepare for life after treatment (Project 3). Project 3 also tests a telephone callback intervention delivered by a cancer information specialist. All participants receive standard print material specific to each project. Preliminary results from the 2-month follow-up interviews are reported for the initial wave of enrolled participants, most of whom were recruited from the Cancer Information Service (1-800-4-CANCER) telephone information program (Project 1: n =208; Project 2: n =340; Project 3: n =792). Self-reported use of the multimedia program was 51%, 52%, and 67% for Projects 1, 2, and 3, respectively. Self-reported use of the print materials (read all, most, or some) was 90%, 85%, and 83% for Projects 1, 2, and 3, respectively. The callback intervention was completed by 92% of Project 3 participants. Among those using the Cancer Information Service Research Consortium interventions, perceived usefulness and benefit was high, and more than 90% reported that they would recommend them to other cancer patients. The authors present 5 initial lessons learned that may help inform future cancer communications research.

Background: Barriers to timely resolution of abnormal cancer screening tests add to cancer health disparities among low-income, uninsured, and minority populations. We conducted a randomized trial to evaluate the impact of lay patient navigators on time to resolution and completion of follow-up testing among patients with abnormal screening tests in a medically underserved patient population., Methods: Denver Health, the safety-net health care system serving Denver, is one of 10 performance sites participating in the Patient Navigation Research Program. Of 993 eligible subjects with abnormal screening tests randomized to navigation and no-navigation (control) arms and analyzed, 628 had abnormal breast screens (66 abnormal clinical breast examinations, 304 BIRADS 0, 200 BIRADS 3, 58 BIRADS 4 or 5) whereas 235 had abnormal colorectal and 130 had abnormal prostate screens., Results: Time to resolution was significantly shorter in the navigated group (stratified log rank test, P < 0.001). Patient navigation improved diagnostic resolution for patients presenting with mammographic BIRADS 3 (P = 0.0003) and BIRADS 0 (P = 0.09), but not BIRADS 4/5 or abnormal breast examinations. Navigation shortened the time for both colorectal (P = 0.0017) and prostate screening resolution (P = 0.06). Participant demographics included 72% minority, 49% with annual household income less than $10,000, and 36% uninsured., Conclusions: Patient navigation positively impacts time to resolution of abnormal screening tests for breast, colorectal, and prostate cancers in a medically underserved population., Impact: By shortening the time to and increasing the proportion of patients with diagnostic resolution patient navigation could reduce disparities in stage at diagnosis and improve cancer outcomes., (2012 AACR)

Background: The Patient Navigation Research Program (PNRP) is a cooperative effort of nine research projects, with similar clinical criteria but with different study designs. To evaluate projects such as PNRP, it is desirable to perform a pooled analysis to increase power relative to the individual projects. There is no agreed-upon prospective methodology, however, for analyzing combined data arising from different study designs. Expert opinions were thus solicited from the members of the PNRP Design and Analysis Committee., Purpose: To review possible methodologies for analyzing combined data arising from heterogeneous study designs., Methods: The Design and Analysis Committee critically reviewed the pros and cons of five potential methods for analyzing combined PNRP project data. The conclusions were based on simple consensus. The five approaches reviewed included the following: (1) analyzing and reporting each project separately, (2) combining data from all projects and performing an individual-level analysis, (3) pooling data from projects having similar study designs, (4) analyzing pooled data using a prospective meta-analytic technique, and (5) analyzing pooled data utilizing a novel simulated group-randomized design., Results: Methodologies varied in their ability to incorporate data from all PNRP projects, to appropriately account for differing study designs, and to accommodate differing project sample sizes., Limitations: The conclusions reached were based on expert opinion and not derived from actual analyses performed., Conclusions: The ability to analyze pooled data arising from differing study designs may provide pertinent information to inform programmatic, budgetary, and policy perspectives. Multisite community-based research may not lend itself well to the more stringent explanatory and pragmatic standards of a randomized controlled trial design. Given our growing interest in community-based population research, the challenges inherent in the analysis of heterogeneous study design are likely to become more salient. Discussion of the analytic issues faced by the PNRP and the methodological approaches we considered may be of value to other prospective community-based research programs.

Purpose: Colon cancer overall survival (OS) is usually computed from the time of diagnosis. Survival gives the initial prognosis but does not reflect how prognosis changes with changing hazard rates over time. Conditional survival (probability of surviving y additional years given they have survived x years [CS or OS|OS]) is an alternative measure that accounts for elapsed time since diagnosis, providing more relevant prognostic information. We extend the concept of CS to condition on the set of patients alive, recurrence-free, and second primary cancer-free (disease-free survival [OS|DFS])., Patients and Methods: Using data from National Surgical Adjuvant Breast and Bowel Project trials C-03 through C-07, 5-year OS|DFS was calculated on patients who were disease free up to 5 years after diagnosis, stratified by age, stage, nodal status, and performance status (PS)., Results: For stage II, OS|DFS improved from 87% to 92% at 5 years. For stage III, OS|DFS improved from 69% to 88%. Patients younger than 50 years showed OS|DFS improvement from 79% to 95%; those older than 70 years showed no sustained increase in OS|DFS. Node-negative patients with > or = 12 nodes resected showed little change (89% to 94%); those with more than four positive nodes showed an improvement (57% to 86%). Patients with a PS of 0 or 1 demonstrated a small improvement; those with a PS of 2 did not (64% to 58%)., Conclusion: Prognosis improves over time for almost all groups of patients with colon cancer, especially those with positive nodes. OS|DFS is a more relevant measure of prognosis for those who have already survived disease free a period of time after diagnosis.

Background: Patient, provider, and systems barriers contribute to delays in cancer care, a lower quality of care, and poorer outcomes in vulnerable populations, including low-income, underinsured, and racial/ethnic minority populations. Patient navigation is emerging as an intervention to address this problem, but navigation requires a clear definition and a rigorous testing of its effectiveness. Pilot programs have provided some evidence of benefit, but have been limited by evaluation of single-site interventions and varying definitions of navigation. To overcome these limitations, a 9-site National Cancer Institute Patient Navigation Research Program (PNRP) was initiated., Methods: The PNRP is charged with designing, implementing, and evaluating a generalizable patient navigation program targeting vulnerable populations. Through a formal committee structure, the PNRP has developed a definition of patient navigation and metrics to assess the process and outcomes of patient navigation in diverse settings, compared with concurrent continuous control groups., Results: The PNRP defines patient navigation as support and guidance offered to vulnerable persons with abnormal cancer screening or a cancer diagnosis, with the goal of overcoming barriers to timely, quality care. Primary outcomes of the PNRP are 1) time to diagnostic resolution; 2) time to initiation of cancer treatment; 3) patient satisfaction with care; and 4) cost effectiveness, for breast, cervical, colon/rectum, and/or prostate cancer., Conclusions: The metrics to assess the processes and outcomes of patient navigation have been developed for the NCI-sponsored PNRP. If the metrics are found to be valid and reliable, they may prove useful to other investigators.

First implemented in 1990, patient navigation interventions are emerging today as an approach to reduce cancer disparities. However, there is lack of consensus about how patient navigation is defined, what patient navigators do, and what their qualifications should be. Little is known about the efficacy and cost-effectiveness of patient navigation. For this review, the authors conducted a qualitative synthesis of published literature on cancer patient navigation. By using the keywords 'navigator' or 'navigation' and 'cancer,' 45 articles were identified in the PubMed database and from reference searches that were published or in press through October 2007. Sixteen studies provided data on the efficacy of navigation in improving timeliness and receipt of cancer screening, diagnostic follow-up care, and treatment. Patient navigation services were defined and differentiated from other outreach services. Overall, there was evidence of some degree of efficacy for patient navigation in increasing participation in cancer screening and adherence to diagnostic follow-up care after the detection of an abnormality. The reported increases in screening ranged from 10.8% to 17.1%, and increases in adherence to diagnostic follow-up care ranged from 21% to 29.2% compared with control patients. There was less evidence regarding the efficacy of patient navigation in reducing either late-stage cancer diagnosis or delays in the initiation of cancer treatment or improving outcomes during cancer survivorship. There were methodological limitations in most studies, such as a lack of control groups, small sample sizes, and contamination with other interventions. Although cancer-related patient navigation interventions are being adopted increasingly across the United States and Canada, further research will be necessary to evaluate their efficacy and cost-effectiveness in improving cancer care., ((c) 2008 American Cancer Society.)

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.

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.

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.

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.

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.

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.

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.

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.

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)

The anemia of chronic renal disease has been attributed primarily to a decrease in erythropoietin (EP) production. Results of this study show that measurable levels of plasma EP can be demonstrated in a majority of patients with end-stage renal failure who are undergoing long-term hemodialysis. These levels were not related to the type of renal disease, nor were they greatly affected by androgenic therapy or by nephrectomy. Although EP elevations in such patients were somewhat less than in nonuremic patients with comparable anemia, the presence of measurable EP levels suggests that impaired end-organ response may play a role in the anemia of chronic renal failure.

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.

Eleven patients with advanced multiple myeloma refractory to standard chemotherapy were treated with a regimen of sequential hemi-body radiotherapy consisting of 800 rad midplane in a single dose to each half. 9/10 patients experienced significant relief of skeletal pain and there were 5/11 objective tumor responses with one complete remission. Treatment-related morbidity was significant and consisted primarily of nausea and emesis, bone marrow suppression, and pneumonitis. This therapy is helpful in the management of advanced myeloma, and should be studied earlier in the course of the disease.

Nineteen patients with advanced refractory lymphoma and 12 patients with acute leukemia, including seven in blastic crisis of chronic myelogenous leukemia (CML), were treated with vindesine in combination with prednisone. Of 16 evaluable patients with lymphocytic or histiocytic lymphoma, one achieved complete remission (6%) and eight achieved partial remissions (50%). Median duration of response was 12 weeks (range, 4-72+). Four of six evaluable patients in blastic crisis of CML showed definite improvement in blood cell counts and symptoms. The major dose-limiting toxic effect was bone marrow suppression, while neurotoxicity was seldom cause for dose modification. The study shows vindesine and prednisone to be active in heavily pretreated patients with non-Hodgkin's lymphoma and blastic phase of CML.

Cytarabine and thioguanine therapy for acute myelocytic leukemia, initiated during the 26th week of pregnancy, led to complete remission of the leukemia in a 22-year-old woman, and allowed for delivery of a normal infant at term. No chromosomal abnormalities were detected in the infant. Cytarabine and thioguanine in combination are effective agents in the treatment of acute leukemia in adults. Their use appears warranted in pregnant patients after the first trimester.

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.

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.

An 18-year-old man presented initially with findings compatible with disseminated intravascular coagulation. Following a brief partial response to intravenous heparin therapy rapid deterioration of renal function was associated with evidence of a hypercoagulable state characterized primarily by excessive platelet aggregation and sequestration. Initiation of aspirin therapy led to a prompt rise in the platelet count and permanent improvement in renal function.

Erythrocyte sedimentation rate (ESR) determinations performed by the Wintrobe method were correlated with a newer, rapid method, the zeta sedimentation ratio (ZSR), in 189 adult patients. Good correlation between the two methods was achieved over a wide range of values, with a correlation coefficient of 0.88 in female and 0.92 in male subjects. The precision of each method was evaluated by performing ten replicate determinations for 11 patients. The average variance for the ZSR was 2.91%, compared with 7.04% for the Wintrobe ESR; a difference significant at p < 0.01. Good correlation with standard methods, speed of performance and superior precision make the ZSR an attractive alternate procedure for the determination of the sedimentation rate.

Cytochemical reactions with a panel of special stains were explored in peripheral blood and lymph node cells of animals with the adult, calf, and thymic types of bovine lymphosarcoma as well as lymphosarcoma in sheep induced with the bovine leukosis virus. These results were compared with normal lymphoid cells. Cytochemical methods included Sudan black B, periodic acid-Schiff, acid phosphatase and three esterases. Cells from ovine lymphosarcomas and a thymic type of bovine lymphosarcoma were distinctively positive to the alpha naphthyl acetate esterase reaction. These cytochemical reactions which were obtained with standard cytochemical methods should aid in the characterization and classification of lymphoproliferative disorders in animals, especially when combined with immunologic surface markers.

Infiltration of the prostate by acute granulocytic leukemia can cause diagnostic and therapeutic difficulties. After stabilization of hematologic findings, the diagnosis can be made safely by needle biopsy of the prostate. The prostate may be one of the so-called sanctuary areas where chemotherapy does not affect the leukemic infiltrate. This process may be a source of reactivation of leukemia in patients who had achieved a hematologic remission. This report describes a patient who had successful eradication of acute myelomonocytic leukemia from the prostate by radiation therapy while in hematologic remission. Better surveillance for leukemic infiltrate of the prostate is needed, including needle biopsy when appropriate. Radiation may be an effective therapy for this manifestation of leukemia.

A case report of a patient with lymphomatoid granulomatosis presenting initially as a reactivated Epstein-Barr virus infection is presented. Epstein-Barr virus is proposed in the possible role of establishing of an immunologically compromised state that may have set the stage for dissemination of this disease process. Of interest is the fact that successful chemotherapeutic management of the disease was accomplished using prednisone and cyclophosphamide. Furthermore, this clinical success was reflected in a decreasing Epstein-Barr virus early antigen-antibody titers accompanied by increasing antivirus capsid antigen titers; hence, it appears that laboratory markers of the response of lymphomatoid granulomatosis to treatment are available in the form of soluble immune complexes, antibodies to Epstein-Barr virus-coded antigens early antigens, Epstein-Barr nuclear antigens and/or virus capsid antigens as well as the active E rosette assay for T-cells. Finally, these data, although supporting the role of Epstein-Barr virus in the pathogenesis of lymphomatoid granulomatosis, suggest the need for further study in additional patients to verify the results.

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.

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.