Emergency Department Use in Adolescent and Young Adult Cancer Early Survivors from 2006 to 2020.

Purpose: Understanding emergency department (ED) use in adolescent and young adult (AYA) survivors could identify gaps in AYA survivorship. Methods: We conducted a cohort study of 7925 AYA survivors (aged 15-39 years at diagnosis) who were 2-5 years from diagnosis in 2006-2020 at Kaiser Permanente Southern California. We calculated ED utilization rates overall and by indication of the encounter (headache, cardiac issues, and suicide attempts). We estimated rate changes by survivorship year and patient factors associated with ED visit using a Poisson model. Results: Cohort was 65.4% women, 45.8% Hispanic, with mean age at diagnosis at 31.3 years. Overall, 38% of AYA survivors had ≥1 ED visit (95th percentile: 5 ED visits). Unadjusted ED rates declined from 374.2/1000 person-years (PY) in Y2 to 327.2 in Y5 (p change < 0.001). Unadjusted rates declined for headache, cardiac issues, and suicide attempts. Factors associated with increased ED use included: age 20-24 at diagnosis [relative risk (RR) = 1.30, 95% CI 1.09-1.56 vs. 35-39 years]; female (RR = 1.27, 95% CI 1.11-1.47 vs. male); non-Hispanic Black race/ethnicity (RR 1.64, 95% CI 1.38-1.95 vs. non-Hispanic white); comorbidity (RR = 1.34, 95% CI 1.16-1.55 for 1 and RR 1.80, 95% CI 1.40-2.30 for 2+ vs. none); and public insurance (RR = 1.99, 95% CI 1.70-2.32 vs. private). Compared with thyroid cancer, cancers associated with increased ED use were breast (RR = 1.45, 95% CI 1.24-1.70), cervical (RR = 2.18, 95% CI 1.76-2.71), colorectal (RR = 2.34, 95% CI 1.94-2.81), and sarcoma (RR = 1.39, 95% CI 1.03-1.88). Conclusion: ED utilization declined as time from diagnosis elapsed, but higher utilization was associated with social determinants of health and cancer types.

Barriers to hydroxyurea use from the perspectives of providers, individuals with sickle cell disease, and families: Report from a U.S. regional collaborative.

Sickle cell disease (SCD) is an inherited blood disorder that affects about 100,000 people in the U.S., primarily Blacks/African-Americans. A multitude of complications negatively impacts quality of life. Hydroxyurea has been FDA approved since 1998 as a disease-modifying therapy for SCD, but is underutilized. Negative and uninformed perceptions of hydroxyurea and barriers to its use hinder adherence and promotion of the medication. As the largest real-world study to date that assessed hydroxyurea use for children and adults with SCD, we gathered and analyzed perspectives of providers, individuals with SCD, and families. Participants provided information about socio-demographics, hospital and emergency admissions for pain, number of severe pain episodes interfering with daily activities, medication adherence, and barriers to hydroxyurea. Providers reported on indications for hydroxyurea, reasons not prescribed, and current laboratory values. We found that hydroxyurea use was reported in over half of eligible patients from this large geographic region in the U.S., representing a range of sickle cell specialty clinical settings and practices. Provider and patient/caregiver reports about hydroxyurea use were consistent with one another; adults 26 years and older were least likely to be on hydroxyurea; and the likelihood of being on hydroxyurea decreased with one or more barriers. Using the intentional and unintentional medication nonadherence framework, we found that, even for patients on hydroxyurea, challenges to taking the medicine at the right time and forgetting were crucial unintentional barriers to adherence. Intentional barriers such as worry about side effects and "tried and it did not work" were important barriers for young adults and adults. For providers, diagnoses other than HgbSS or HgbS-ß0 thalassemia were associated with lower odds of prescribing, consistent with evidence-based guidelines. Our results support strengthening provider understanding and confidence in implementing existing SCD guidelines, and the importance of shared decision making. Our findings can assist providers in understanding choices and decisions of families; guide individualized clinical discussions regarding hydroxyurea therapy; and help with developing tailored interventions to address barriers. Addressing barriers to hydroxyurea use can inform strategies to minimize similar barriers in the use of emerging and combination therapies for SCD.

An evaluation of patient-reported outcomes in sickle cell disease within a conceptual model.

PURPOSE: To examine the relations between patient-reported outcomes (PROs) within a conceptual model for adults with sickle cell disease (SCD) ages 18 - 45 years enrolled in the multi-site Sickle Cell Disease Implementation Consortium (SCDIC) registry. We hypothesized that patient and SCD-related factors, particularly pain, and barriers to care would independently contribute to functioning as measured using PRO domains. METHODS: Participants (N = 2054) completed a 48-item survey including socio-demographics and PRO measures, e.g., social functioning, pain impact, emotional distress, and cognitive functioning. Participants reported on lifetime SCD complications, pain episode frequency and severity, and barriers to healthcare. RESULTS: Higher pain frequency was associated with higher odds of worse outcomes in all PRO domains, controlling for age, gender and site (OR range 1.02-1.10, 95% CI range [1.004-1.12]). Reported history of treatment for depression was associated with 5 of 7 PRO measures (OR range 1.58-3.28 95% CI range [1.18-4.32]). Fewer individual barriers to care and fewer SCD complications were associated with better outcomes in the emotion domain (OR range 0.46-0.64, 95% CI range [0.34-0.86]). CONCLUSIONS: Study results highlight the importance of the biopsychosocial model to enhance understanding of the needs of this complex population, and to design multi-dimensional approaches for providing more effective interventions to improve outcomes.

In vivo fermentation production of humanized noncoding RNAs carrying payload miRNAs for targeted anticancer therapy.

Rationale: Noncoding RNAs (ncRNAs) such as microRNAs (miRs or miRNAs) play important roles in the control of cellular processes through posttranscriptional gene regulation. However, ncRNA research is limited to utilizing RNA agents synthesized in vitro. Recombinant RNAs produced and folded in living cells shall better recapitulate biologic RNAs. Methods: Herein, we developed a novel platform for in vivo fermentation production of humanized recombinant ncRNA molecules, namely hBERAs, carrying payload miRNAs or siRNAs. Target hBERAs were purified by anion exchange FPLC method. Functions of hBERA/miRNAs were investigated in human carcinoma cells and antitumor activities were determined in orthotopic osteosarcoma xenograft spontaneous lung metastasis mouse models. Results: Proper human tRNAs were identified to couple with optimal hsa-pre-miR-34a as new fully-humanized ncRNA carriers to accommodate warhead miRNAs or siRNAs. A group of 30 target hBERAs were all heterogeneously overexpressed (each accounting for >40% of total bacterial RNA), which facilitated large-scale production (8-31 mg of individual hBERAs from 1L bacterial culture). Model hBERA/miR-34a-5p and miR-124-3p were selectively processed to warhead miRNAs in human carcinoma cells to modulate target gene expression, enhance apoptosis and inhibit invasiveness. In addition, bioengineered miR-34a-5p and miR-124-3p agents both reduced orthotopic osteosarcoma xenograft tumor growth and spontaneous pulmonary metastases significantly. Conclusion: This novel ncRNA bioengineering technology and resulting recombinant ncRNAs are unique additions to conventional technologies and tools for basic research and drug development.

American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease.

BACKGROUND: Prevention and management of end-organ disease represent major challenges facing providers of children and adults with sickle cell disease (SCD). Uncertainty and variability in the screening, diagnosis, and management of cardiopulmonary and renal complications in SCD lead to varying outcomes for affected individuals. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD. METHODS: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews up to September 2017. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 10 recommendations for screening, diagnosis, and management of cardiopulmonary and renal complications of SCD. Recommendations related to anticoagulation duration for adults with SCD and venous thromboembolism were also developed. CONCLUSIONS: Most recommendations were conditional due to a paucity of direct, high-quality evidence for outcomes of interest. Future research was identified, including the need for prospective studies to better understand the natural history of cardiopulmonary and renal disease, their relationship to patient-important outcomes, and optimal management.

Bioengineered Noncoding RNAs Selectively Change Cellular miRNome Profiles for Cancer Therapy.

Noncoding RNAs (ncRNAs) produced in live cells may better reflect intracellular ncRNAs for research and therapy. Attempts were made to produce biologic ncRNAs, but at low yield or success rate. Here we first report a new ncRNA bioengineering technology using more stable ncRNA carrier (nCAR) containing a pre-miR-34a derivative identified by rational design and experimental validation. This approach offered a remarkable higher level expression (40%-80% of total RNAs) of recombinant ncRNAs in bacteria and gave an 80% success rate (33 of 42 ncRNAs). New FPLC and spin-column based methods were also developed for large- and small-scale purification of milligrams and micrograms of recombinant ncRNAs from half liter and milliliters of bacterial culture, respectively. We then used two bioengineered nCAR/miRNAs to demonstrate the selective release of target miRNAs into human cells, which were revealed to be Dicer dependent (miR-34a-5p) or independent (miR-124a-3p), and subsequent changes of miRNome and transcriptome profiles. miRNA enrichment analyses of altered transcriptome confirmed the specificity of nCAR/miRNAs in target gene regulation. Furthermore, nCAR assembled miR-34a-5p and miR-124-3p were active in suppressing human lung carcinoma cell proliferation through modulation of target gene expression (e.g., cMET and CDK6 for miR-34a-5p; STAT3 and ABCC4 for miR-124-3p). In addition, bioengineered miRNA molecules were effective in controlling metastatic lung xenograft progression, as demonstrated by live animal and ex vivo lung tissue bioluminescent imaging as well as histopathological examination. This novel ncRNA bioengineering platform can be easily adapted to produce various ncRNA molecules, and biologic ncRNAs hold the promise as new cancer therapeutics.

Co-targeting of DNA, RNA, and protein molecules provides optimal outcomes for treating osteosarcoma and pulmonary metastasis in spontaneous and experimental metastasis mouse models.

Metastasis is a major cause of mortality for cancer patients and remains as the greatest challenge in cancer therapy. Driven by multiple factors, metastasis may not be controlled by the inhibition of single target. This study was aimed at assessing the hypothesis that drugs could be rationally combined to co-target critical DNA, RNA and protein molecules to achieve "saturation attack" against metastasis. Independent actions of the model drugs DNA-intercalating doxorubicin, RNA-interfering miR-34a and protein-inhibiting sorafenib on DNA replication, RNA translation and protein kinase signaling in highly metastatic, human osteosarcoma 143B cells were demonstrated by the increase of γH2A.X foci formation, reduction of c-MET expression and inhibition of Erk1/2 phosphorylation, respectively, and optimal effects were found for triple-drug combination. Consequently, triple-drug treatment showed a strong synergism in suppressing 143B cell proliferation and the greatest effects in reducing cell invasion. Compared to single- and dual-drug treatment, triple-drug therapy suppressed pulmonary metastases and orthotopic osteosarcoma progression to significantly greater degrees in orthotopic osteosarcoma xenograft/spontaneous metastases mouse models, while none showed significant toxicity. In addition, triple-drug therapy improved the overall survival to the greatest extent in experimental metastases mouse models. These findings demonstrate co-targeting of DNA, RNA and protein molecules as a novel therapeutic strategy for the treatment of metastasis.

Bioengineering Novel Chimeric microRNA-34a for Prodrug Cancer Therapy: High-Yield Expression and Purification, and Structural and Functional Characterization.

Development of anticancer treatments based on microRNA (miRNA/miR) such as miR-34a replacement therapy is limited to the use of synthetic RNAs with artificial modifications. Herein, we present a new approach to a high-yield and large-scale biosynthesis, in Escherichia coli using transfer RNA (tRNA) scaffold, of chimeric miR-34a agent, which may act as a prodrug for anticancer therapy. The recombinant tRNA fusion pre-miR-34a (tRNA/mir-34a) was quickly purified to a high degree of homogeneity (>98%) using anion-exchange fast protein liquid chromatography, whose primary sequence and post-transcriptional modifications were directly characterized by mass spectrometric analyses. Chimeric tRNA/mir-34a showed a favorable cellular stability while it was degradable by several ribonucleases. Deep sequencing and quantitative real-time polymerase chain reaction studies revealed that tRNA-carried pre-miR-34a was precisely processed to mature miR-34a within human carcinoma cells, and the same tRNA fragments were produced from tRNA/mir-34a and the control tRNA scaffold (tRNA/MSA). Consequently, tRNA/mir-34a inhibited the proliferation of various types of human carcinoma cells in a dose-dependent manner and to a much greater degree than the control tRNA/MSA, which was mechanistically attributable to the reduction of miR-34a target genes. Furthermore, tRNA/mir-34a significantly suppressed the growth of human non-small-cell lung cancer A549 and hepatocarcinoma HepG2 xenograft tumors in mice, compared with the same dose of tRNA/MSA. In addition, recombinant tRNA/mir-34a had no or minimal effect on blood chemistry and interleukin-6 level in mouse models, suggesting that recombinant RNAs were well tolerated. These findings provoke a conversation on producing biologic miRNAs to perform miRNA actions, and point toward a new direction in developing miRNA-based therapies.

Polyurethane shape-memory polymers demonstrate functional biocompatibility in vitro.

Shape memory polymers (SMPs) are a class of polymeric materials used in various medical interventions such as vascular stents. In this work, two SMPs, thermoplastic (TP) and thermoset (TS), have been measured in vitro for the degree of cellular and protein adhesion, their ability to stimulate inflammatory cytokine production, as well as the effects of the SMPs on the haemostatic system. The stimulatory properties of SMPs on neutrophils have also been directly addressed. Based on the studies of SMP biocompatibility as defined by inflammation, thrombogenesis, and the activation of both platelets and neutrophils, the TS and TP SMP materials are unlikely to stimulate an inflammatory response in vivo. [figure: see text]

Incidence of venous thromboembolism and the impact on survival in breast cancer patients.

PURPOSE: The incidence of venous thromboembolism (VTE) and the risk factors associated with development of VTE have not been reported in a large population-based study of breast cancer patients. PATIENTS AND METHODS: The California Cancer Registry was merged with the Patient Discharge Data Set, and the number of VTE events determined among patients diagnosed between 1993 and 1999. RESULTS: Among 108,255 patients with breast cancer, the 2-year cumulative VTE incidence was 1.2%, with a rate of 1.2 and 0.6 events/100 patient-years during the first and second half-year, respectively. The 1-year incidence of VTE was significantly increased compared with the general population (standardized incidence ratio of VTE, 4.2; 95% CI, 3.9 to 4.4). In a multivariate model, significant predictors of developing VTE within 2 years were: age (hazard ratio [HR], 2.0 if > 75 years v < 45; 95% CI, 1.6 to 2.6), the number of chronic medical comorbidities (HR, 2.9 if 3 v 0; 95% CI, 2.4 to 3.5), and advancing cancer stage (HR, 6.3; 95% CI, 5.3 to 7.5 for metastatic v local disease). In multivariate models, VTE was a significant predictor of decreased 2-year survival (HR, 2.3; 95% CI, 2.1 to 2.6) and when stratified by initial cancer stage, the effect was highest in patients with localized (HR, 5.1; 95% CI, 3.6 to 7.1) or regional stage (HR, 3.5; 95% CI, 2.5 to 4.8) cancer compared with patients with metastatic disease (HR, 1.9; 95% CI, 1.5 to 2.4). CONCLUSION: Approximately 1% of breast cancer patients developed VTE within 2 years, with the highest incidence in the first 6 months after diagnosis. Metastatic disease and comorbidities were the strongest predictors. The diagnosis of VTE was associated with a higher risk of death within 2 years.

Incidence of venous thromboembolism and its effect on survival among patients with common cancers.

BACKGROUND: The incidence of venous thromboembolism after diagnosis of specific cancers and the effect of thromboembolism on survival are not well defined. METHODS: The California Cancer Registry was linked to the California Patient Discharge Data Set to determine the incidence of venous thromboembolism among cancer cases diagnosed between 1993 and 1995. The incidence and timing of thromboembolism within 1 and 2 years of cancer diagnosis and the risk factors associated with thromboembolism and death were determined. RESULTS: Among 235 149 cancer cases, 3775 (1.6%) were diagnosed with venous thromboembolism within 2 years, 463 (12%) at the time cancer was diagnosed and 3312 (88%) subsequently. In risk-adjusted models, metastatic disease at the time of diagnosis was the strongest predictor of thromboembolism. Expressed as events per 100 patient-years, the highest incidence of thromboembolism occurred during the first year of follow-up among cases with metastatic-stage pancreatic (20.0), stomach (10.7), bladder (7.9), uterine (6.4), renal (6.0), and lung (5.0) cancer. Adjusting for age, race, and stage, diagnosis of thromboembolism was a significant predictor of decreased survival during the first year for all cancer types (hazard ratios, 1.6-4.2; P<.01). CONCLUSIONS: The incidence of venous thromboembolism varied with cancer type and was highest among patients initially diagnosed with metastatic-stage disease. The incidence rate of thromboembolism decreased over time. Diagnosis of thromboembolism during the first year of follow-up was a significant predictor of death for most cancer types and stages analyzed. For some types of cancer, the incidence of thromboembolism was sufficiently high to warrant prospective clinical trials of primary thromboprophylaxis.

B cell reductive therapy in the treatment of autoimmune diseases: a focus on monoclonal antibody treatment of rheumatoid arthritis.

The therapeutic approach to patients with autoimmune disorders is in the midst of a dramatic change. Monoclonal antibody technology has allowed us to dissect and now manipulate the human immune system with greater precision. It is now widely recognized that B lymphocytes play a role in the pathogenesis of many autoimmune diseases, though the extent and contribution is a matter of debate and active investigation. There is emerging data to suggest that both antibody-dependent and independent mechanisms contribute to disease pathogenesis. However, given the heterogeneous nature of autoimmune diseases, and the varied responses to B lymphocyte reduction, the role of B lymphocytes is likely disease-specific. The two clinical trials discussed in this review demonstrate remarkable consistency in the ability of B cell reduction to ameliorate the clinical manifestations of rheumatoid arthritis with minimal toxicity. B lymphocyte targeted approaches to autoimmune disease in general, and RA specifically, will not only provide an effective and potentially less toxic alternative treatment option, but also allow for a better understanding of the pathogenesis of these complex and morbid diseases.

Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults.

BACKGROUND: It is unclear how frequently unprovoked venous thromboembolism (VTE) reflects the presence of an occult cancer. METHODS: The California Cancer Registry was used to identify diagnosed cases of 19 common malignancies during a 6-year period. Cases were linked to a hospital discharge database to identify incident VTE events in the year before the cancer diagnosis date. The standardized incidence ratio (SIR) of unprovoked VTE was determined by using the age-, race-, and sex-specific incidence rates in California. RESULTS: Among 528,693 cancer cases, 596 (0.11%) were associated with a diagnosis of unprovoked VTE within 1 year of the cancer diagnosis, compared with 443.0 expected cases (SIR, 1.3; 95% confidence interval, 1.2-1.5; P<.001). Among cases with metastatic-stage cancer, the SIR was 2.3 (95% confidence interval, 2.0-2.6; P<.001), whereas for all other stages, the SIR was 1.07 (95% confidence interval, 0.97-1.18; P = .09). The incidence of preceding VTE was increased over that expected only during the 4-month period immediately preceding the cancer diagnosis date (P<.001). Only 7 cancer types were associated with a significantly elevated SIR: acute myelogenous leukemia; non-Hodgkin lymphoma; and renal cell, ovarian, pancreatic, stomach, and lung cancer (SIR range, 1.8-4.2). CONCLUSIONS: In the year preceding the diagnosis of cancer, the number of cases with unprovoked VTE was modestly higher than expected, and almost all of the unexpected VTE cases were associated with a diagnosis of metastatic-stage cancer within 4 months. Given the timing and advanced stage of the unexpected cases, it is unlikely that earlier diagnosis of these cancers would have significantly improved long-term survival.

An evaluation of barriers to accrual in the era of legislation requiring insurance coverage of cancer clinical trial costs in California.

PURPOSE: Clinical trials are essential to improve cancer therapy, but only 3% of newly diagnosed adult cancer patients enroll annually. We previously conducted a prospective analysis of factors affecting trial accrual at the UC Davis Cancer Center between 1997 and 2000. It was found that the accrual rate was 14% and that patients with private insurance were significantly less likely than patients with government insurance to enroll, suggesting that fear of insurance denial was a barrier. In 2002, a new California law (SB37) required insurers to reimburse routine costs of care for cancer trials. METHODS: To assess the impact of SB37 on accrual, we repeated our study using the same sur vey instrument. Oncologists seeing new patients at the UC Davis Cancer Center from August to November 2002 completed questionnaires that inquired about patient characteristics and eligibility, protocol availability, and patient willingness to participate. RESULTS: Physicians considered clinical trials for 55% (118/216) of patients, but trials were available for only 53% (62/118). Eligibility criteria were met by 82% (51/62). Of these, 69% (35/51) agreed to participate (vs 51% previously). No patient declined to participate because of insurance limitations (vs 8% previously). Furthermore, insurance type was no longer a significant factor in determining whether patients would enroll. This suggests that although the overall rate of accrual is only slightly increased after passage of SB37, patients may be more willing to enroll. Efforts to increase participation must include enhancing physician and patient awareness of SB37.

Blastic mantle cell lymphoma developing concurrently in a patient with chronic myelogenous leukemia and a review of the literature.

Non-Hodgkin's lymphoma (NHL) occurring as a synchronous malignancy with chronic myelogenous leukemia (CML) is rare. To our knowledge, this is the first case reported of a patient who developed mantle cell lymphoma (MCL) after therapy with imatinib mesylate for CML. After a 3-year history of CML, the patient developed a lymphocytosis associated with diarrhea, anorexia, and weight loss. Imaging studies revealed abdominal adenopathy and extensive lymphomatous infiltration of the liver, stomach, pancreas, and kidneys. Flow cytometric and cytogenetic studies were consistent with MCL. Fluorescence in situ hybridization (FISH) of the bone marrow revealed a genetically distinct lymphoid neoplasm rather than an extramedullary blast crisis of CML. The development of lung cancer, prostate cancer, CML and MCL in this patient suggests a genetic predisposition, although other factors, including environmental exposures and therapy with imatinib mesylate could have had a contributory or synergistic role in the development of MCL.

Early diagnosis and successful treatment of a patient with transfusion-associated GVHD with autologous peripheral blood progenitor cell transplantation.

BACKGROUND: Transfusion-associated GVHD (TA-GVHD) is an uncommon complication of blood transfusion. Diagnosis of TA-GVHD is difficult, and it is usually rapidly fatal. There are few documented sur- vivors of TA-GVHD. CASE REPORT: A 61-year-old woman with chronic lymphocytic leukemia (CLL) was treated with fludarabine followed by combination chemotherapy and high-dose radioimmunotherapy and peripheral blood progenitor cell (PBPC) rescue. She was transfused with nonirradiated blood components at an outside hospital and presented 10 days later with rash, elevated liver enzymes, and progressive pancytopenia. Skin biopsy was consistent with GVHD, and HLA typing of lymphocytes from the patient demonstrated mixed chimerism. The patient was treated with solumedrol and cyclosporin A, followed by high-dose cyclophosphamide and antithymocyte globulin and autologous PBPC infusion. She had rapid engraftment, resolution of skin rash, and normalization of liver function abnormalities. She is in good health with normal blood counts and no evidence of CLL 34 months after transplantation. CONCLUSION: TA-GVHD occurs in the setting of an immunocompromised recipient receiving nonirradiated blood components. A typical presentation includes skin rash, liver function abnormalities, and pancytopenia. Demonstration of mixed chimerism by HLA typing facilitated diagnosis in this patient. High-dose immunosuppression, facilitated by the availability of autologous PBPCs, resulted in a successful outcome.

Postprandial lipemia is associated with platelet and monocyte activation and increased monocyte cytokine expression in normolipemic men.

The activation of platelets and monocytes has been implicated in the development of cardiovascular diseases. We asked the question if postprandial lipemia following a fat- containing meal is associated with platelet and monocyte activation and increased platelet-monocyte interaction. Thirteen healthy, normal weight, normolipemic males, 20 to 49 years, consumed a 40% fat meal of whole foods. Blood samples were obtained at fasting and 3 1/2 and 6 hours after ingestion. Triglyceride levels increased to 48% over baseline at 3 1/2 hours postconsumption and returned to fasting levels by 6 hours. Multiparameter flow cytometry using monoclonal antibodies showed that the percentage of platelets expressing surface P-selectin and the activated conformation the GPIIb-IIa receptor was significantly higher at 3 1/2 hours compared to fasting. The percentage of platelet-monocyte aggregates increased by 36% at 3 1/2 hours and 43% at 6 hours postconsumption. The percentage of monocytes expressing intracellular tumor necrosis factor-alpha (TNF-alpha) increased seven and eightfold at 3 1/2 and 6 hours, respectively. The expression of interleukin-1beta (IL-1beta increased in a similar manner. These data suggest activation of platelets and monocytes after a moderate fat meal. Repetitive activation of platelets and monocytes could be an early event in the initiation and development of atherosclerosis.