Quality Assessment of Clinical Practice Guidelines on the Treatment of Psoriasis Using the AGREE II Tool. / Evaluación de la calidad de guías de práctica clínica para el tratamiento de psoriasis mediante la herramienta AGREE II.

BACKGROUND: Clinical practice guidelines (CPGs) are designed to help health professionals provide patients with excellent medical care. The last critical appraisal of CPGs on the treatment of psoriasis evaluated publications up to 2009, but several new guidelines have been published since and their methodological quality remains unclear. OBJECTIVE: The aim of this study was to systematically evaluate the quality of CPGs on the treatment of psoriasis published between 2010 and 2020 using the Appraisal Guidelines Research and Evaluation II (AGREE II) tool. MATERIAL AND METHODS: We searched for relevant CPGs in MEDLINE, Embase, and LILACS (Latin American and Caribean Health Sciences Literature) as well as in the gray literature. Two reviewers working independently selected the guidelines for analysis and extracted the relevant data. Each guideline was then assessed using the AGREE II instrument by 5 reviewers, also working independently. RESULTS: Nineteen CPGs met the inclusion criteria and most of them had been produced in high-income countries. The mean (SD) domain scores were 84.9% (14.7%) for scope and purpose, 65.5% (19.3%) for stakeholder involvement, 66.7% (15.6%) for rigor of development, 72.8% (16.8%) for clarity of presentation, 46.6% (21.7%) for applicability, and 57.0% (30.4%) for editorial independence. CONCLUSIONS: Although about three-quarters of the CPGs assessed were judged to be of high quality and over half were recommended for use in clinical practice, standards of guideline development need to be raised to improve CPG quality, particularly in terms of applicability and editorial independence, which had the lowest scores in our evaluation.

Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial.

BACKGROUND: We compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety. METHODS: BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18-70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov, number NCT00688740. FINDINGS: Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90-126), disease-free survival was 62% (95% CI 58-65) for patients in the TAC group and 55% (51-59) for patients in the FAC group (hazard ratio [HR] 0·80, 95% CI 0·68-0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72-79) for patients in the TAC group and 69% (65-72) for patients in the FAC group (HR 0·74, 0·61-0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3-4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC. INTERPRETATION: Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation. FUNDING: Sanofi.

Exosomal pMHC-I complex targets T cell-based vaccine to directly stimulate CTL responses leading to antitumor immunity in transgenic FVBneuN and HLA-A2/HER2 mice and eradicating trastuzumab-resistant tumor in athymic nude mice.

One of the major obstacles in human epidermal growth factor receptor 2 (HER2)-specific trastuzumab antibody immunotherapy of HER2-positive breast cancer is the development of trastuzumab resistance, warranting the search for other therapeutic strategies. Using mouse models, we previously demonstrated that ovalbumin (OVA)-specific dendritic cell (DC)-released exosome (EXOOVA)-targeted CD4(+) T cell-based (OVA-TEXO) vaccine stimulates efficient cytotoxic T lymphocyte (CTL) responses via exosomal peptide/major histocompatibility complex (pMHC)-I, exosomal CD80 and endogenous IL-2 signaling; and long-term CTL memory by means of via endogenous CD40L signaling. In this study, using two-photon microscopy, we provide the first visual evidence on targeting OVA-TEXO to cognate CD8(+) T cells in vivo via exosomal pMHC-I complex. We prepared HER2/neu-specific Neu-TEXO and HER2-TEXO vaccines using adenoviral vector (AdVneu and AdVHER2)-transfected DC (DCneu and DCHER2)-released EXOs (EXOneu and EXOHER2), and assessed their stimulatory effects on HER2/neu-specific CTL responses and antitumor immunity. We demonstrate that Neu-TEXO vaccine is capable of stimulating efficient neu-specific CTL responses, leading to protective immunity against neu-expressing Tg1-1 breast cancer in all 6/6 transgenic (Tg) FVBneuN mice with neu-specific self-immune tolerance. We also demonstrate that HER2-TEXO vaccine is capable of inducing HER2-specific CTL responses and protective immunity against transgene HLA-A2(+)HER2(+) BL6-10A2/HER2 B16 melanoma in 2/8 double Tg HLA-A2/HER2 mice with HER2-specific self-immune tolerance. The remaining 6/8 mice had significantly prolonged survival. Furthermore, we demonstrate that HER2-TEXO vaccine stimulates responses of CD8(+) T cells capable of not only inducing killing activity to HLA-A2(+)HER2(+) BL6-10A2/HER2 melanoma and trastuzumab-resistant BT474A2 breast cancer cells in vitro but also eradicating 6-day palpable HER2(+) BT474A2 breast cancer (3-4 mm in diameter) in athymic nude mice. Therefore, the novel T cell-based HER2-TEXO vaccine may provide a new therapeutic alternative for women with HER2(+) breast cancer, especially for trastuzumab-resistant HER2(+) breast cancer patients.

Outcomes of Rural Men with Breast Cancer: A Multicenter Population Based Retrospective Cohort Study.

BACKGROUND: Breast cancer is rare in men. This population-based study aimed to determine outcomes of male breast cancer in relation to residence and other variables. METHODS: In this retrospective cohort study, men diagnosed with breast cancer in Saskatchewan during 2000-2019 were evaluated. Cox proportional multivariable regression analyses were performed to determine the correlation between survival and clinicopathological and contextual factors. RESULTS: One hundred-eight eligible patients with a median age of 69 years were identified. Of them, 16% had WHO performance status ≥ 2 and 61% were rural residents. The stage at diagnosis was as follows: stage 0, 7%; I, 31%; II, 42%; III, 11%; IV, 8%. Ninety-eight percent had hormone receptor-positive breast cancer. The median disease-free survival of urban patients was 97 (95% CI: 50-143) vs. 64 (46-82) months of rural patients (p = 0.29). The median OS of urban patients was 127 (94-159) vs. 93 (32-153) months for rural patients (p = 0.27). On multivariable analysis, performance status ≥ 2, hazard ratio (HR) 2.82 (1.14-6.94), lack of adjuvant systemic therapy, HR 2.47 (1.03-5.92), and node-positive disease, HR 2.32 (1.22-4.40) were significantly correlated with inferior disease-free survival in early-stage invasive breast cancer. Whereas stage IV disease, HR 7.8 (3.1-19.5), performance status ≥ 2, HR 3.25 (1.57-6.71), and age ≥ 65 years, HR 2.37 (1.13-5.0) were correlated with inferior overall survival in all stages. CONCLUSIONS: Although residence was not significantly correlated with outcomes, rural men had numerically inferior survival. Poor performance status, node-positive disease, and lack of adjuvant systemic therapy were correlated with inferior disease-free survival.

Efficacy of adjuvant trastuzumab in women with HER2-positive T1a or bN0M0 breast cancer: a population-based cohort study.

Adjuvant trastuzumab has been associated with superior survival in women with ≥ T1c or node-positive HER2-positive early-stage breast cancer; however, there is a lack of phase III trials in women with T1a/bN0 disease. Our study aimed to assess the outcomes of women with HER2-positive T1a/bN0 breast cancer who received adjuvant trastuzumab in Saskatchewan, Canada. We evaluated all women diagnosed with HER2-positive T1a/bN0 breast cancer in Saskatchewan between 2008 and 2017. We performed Cox proportional multivariable analysis to determine factors correlated with survival. In addition, inverse probability treatment weighting (IPTW) using propensity score was performed to assess benefit of adjuvant trastuzumab. Ninety-one eligible women with a median age of 61 years (range 30-89) were identified. Thirty-nine (43%) women received adjuvant trastuzumab. Women who received trastuzumab were younger and had a higher rate of T1b disease. Overall, 3% of women who received trastuzumab compared to 12% of women who did not receive trastuzumab developed breast cancer recurrence (p = 0.23). Five-year disease-free survival (DFS) of women who received adjuvant trastuzumab was 94.8% compared to 82.7% of women who did not receive trastuzumab (p = 0.22). Five-year overall survival was 100% of women who received trastuzumab compared to 90.4% of women who did not receive adjuvant trastuzumab (p = 0.038). In the multivariable analysis, grade III tumors were correlated with inferior DFS (hazard ratio [HR] 5.5, 95% CI [1.7-17.7]). The propensity score using the inverse probability of treatment weighting showed that lack of adjuvant trastuzumab was correlated inferior DFS, with an HR of 4 (95% CI 1.05-15.5). Women with HER2-positive T1a/bN0 breast cancer had overall low recurrence of breast cancer. However, the results of this exploratory analysis indicate that women who received adjuvant trastuzumab had better survival.

Current Landscape of Targeted Therapy in Hormone Receptor-Positive and HER2-Negative Breast Cancer.

Background: Hormone receptor-positive and HER2-negative breast cancer (HR + BC) is the most prevalent breast cancer. Endocrine therapy is the mainstay of treatment, however, due to the heterogeneous nature of the disease, resistance to endocrine therapy is not uncommon. Over the past decades, the emergence of novel targeted therapy in combination with endocrine therapy has shown improvement in outcomes of HR + BC. This paper reviews available data of targeted therapy and the results of pivotal clinical trials in the management of HR + BC. Methods: A literature search in PubMed and Google Scholar was performed using keywords related to HR + BC and targeted therapy. Major relevant studies that were presented in international cancer research conferences were also included. Results: Endocrine therapy with tamoxifen and aromatase inhibitors are backbone treatments for women with early-stage HR + BC leading to a significant reduction in mortality. They can also be used for primary prevention in women with a high risk of breast cancer. Preliminary data has shown the efficacy of adjuvant cyclin-dependent kinase (CDK) 4/6 inhibitor, abemaciclib, in high-risk disease in combination with aromatase inhibitors. For most women with advanced HR + BC, endocrine therapy is the primary treatment. Recent evidence has shown that the use of CKD 4/6 inhibitors, mTOR inhibitors, and PI3K inhibitors in combination with endocrine therapy has been associated with better outcomes and delays initiation of chemotherapy. Several novel agents are under study for HR + BC. Discussion: Targeted treatment options for HR + BC have evolved. The future of overcoming resistance to targeted therapy, novel compounds, and predictive markers are key to improving HR + BC outcomes.

Comparison of the Quality of Life of Patients with Breast or Colon Cancer with an Arm Vein Port (TIVAD) Versus a Peripherally Inserted Central Catheter (PICC).

INTRODUCTION: Venous access is a crucial element in chemotherapy delivery. It remains unclear whether cancer patients prefer a port to a peripherally inserted central catheter (PICC). Our study aimed to assess cancer patients' satisfaction with their venous access device and to compare the quality of life (QoL) of subjects with a PICC to those with a port. METHODS: In this prospective cohort study, EORTC QLQ-C30, and a locally developed quality of life survey (QLAVD), designed to assess satisfaction with venous access devices, were administered to breast or colorectal cancer patients over a one-year period following the device insertion. Mixed effects models were used to assess changes on mean scores at different time points. RESULTS: A total of 101 patients were recruited over a three-year period, (PICC group, n = 50; port group, n = 51). Survey response rates for months one and three were 72% and 48%, respectively. Overall, no significant differences were noted between the two groups in relation to EORTC QOL. At three months, the mean pain scores were 3.5 ± 2.3 for the port and 1.3 ± 0.75 for PICC (<0.001). The mean score for a negative effect of the venous access device on psychosocial well-being was 6.0 ± 4.1 for PICC and 3.0 ± 2.7 for the port (p = 0.005). Complications related to PICCs occurred in 38% patients versus 41% with a port (p > 0.24). CONCLUSIONS: Although subjects with a port experienced more pain during the device insertion or access for chemotherapy, it had a smaller negative impact on psychosocial scores than the PICC. No significant differences in complications rates were observed between the two devices.

Efficacy of Fulvestrant in Women with Hormone-Resistant Metastatic Breast Cancer (mBC): A Canadian Province Experience.

INTRODUCTION: Fulvestrant has demonstrated efficacy in hormone receptor positive (HR+) metastatic breast cancer (mBC), both in first-and second-line settings. In clinical practice, however, fulvestrant has been used as a later-line therapy. This study assessed the efficacy of fulvestrant in women with mBC in early-versus later-line therapy. METHODS: This retrospective cohort study assessed Saskatchewan women with HR+ mBC who received fulvestrant between 2003-2019. A multivariate Cox proportional survival analysis was performed. RESULTS: One hundred and eighty-six women with a median age of 63.5 years were identified-178 (95.6%) had hormone-resistant mBC, 57.5% had visceral disease, and 43.0% had received chemotherapy before fulvestrant. 102 (54.8%) women received ≤2-line-therapy, and 84 (45.2%) received ≥3 line-therapy before fulvestrant. The median time to progression (TTP) was 12 months in the early-treatment vs. 6 months in the later-treatment group, p = 0.015. Overall survival (OS) from the start of fulvestrant was 26 months in the early-treatment group vs. 16 months in the later-treatment group, p = 0.067. On multivariate analysis, absence of visceral metastasis, HR: 0.70 (0.50-0.99), was significantly correlated with better TTP, whereas post-fulvestrant chemotherapy, HR: 0.32 (0.23-0.47), clinical benefit from fulvestrant, HR: 0.44 (0.30-0.65), and absence of visceral metastasis, HR: 0.70 (0.50-0.97), were correlated with better OS. CONCLUSIONS: Fulvestrant has demonstrated efficacy as both early-and later-line therapy in hormone-resistant mBC. Our results show that women with clinical benefit from fulvestrant, who received post-fulvestrant chemotherapy, or had non-visceral disease, had better survival.

Early discontinuation but not the timing of adjuvant therapy affects survival of patients with high-risk colorectal cancer: a population-based study.

BACKGROUND: Adjuvant therapy results in significant improvement in survival of patients with high-risk colorectal cancer. Little is known about the significance of timing and early discontinuation of adjuvant treatment in such patients. Our study aims to determine the prognostic impact of timing and completion of adjuvant therapy in patients with high-risk colorectal cancer. METHODS: Medical records of patients with stage III colon and stage II/III rectal cancer diagnosed between 1993 and 2000 in the province of Saskatchewan were reviewed. Cox proportional hazards models were used to analyze the impact of timing and completion of adjuvant therapy on survival. RESULTS: Six hundred sixty-three eligible patients with a median age of 66 years were identified. Sixty-five percent patients received adjuvant <56 days after surgery and 79% patients completed planned treatment. Median follow-up was 54.6 months. Five-year disease-free survival and overall survival of patients who received adjuvant therapy <56 days after surgery was 54.6% and 59.5%, respectively, compared with 51.9% and 57.1%, respectively, of patients who received therapy ≥56 days after surgery (P = NS). The five-year disease disease-free survival and overall survival of patients who completed planned treatment was 56.7% and 62.3%, respectively, compared with 42.1% and 45%, respectively, of patients who required early treatment discontinuation (P < .0001). On multivariate analysis, age ≥65 years, T4 tumor, grade 3 cancer, node-positive disease, rectal tumor, and early treatment discontinuation were identified as poor prognostic factors. CONCLUSIONS: Although time to adjuvant therapy following surgical resection did not impact the outcomes, failure to complete planned therapy was associated with adverse prognosis.

Heterologous human/rat HER2-specific exosome-targeted T cell vaccine stimulates potent humoral and CTL responses leading to enhanced circumvention of HER2 tolerance in double transgenic HLA-A2/HER2 mice.

DNA vaccines composed of heterologous human HER2 and rat neu sequences induce stronger antibody response and protective antitumor immunity than either HER2 or neu DNA vaccines in transgenic mice. We previously developed HER2-specific exosome-targeted T-cell vaccine HER2-TEXO capable of stimulating HER2-specific CD8+ T-cell responses, but only leading to partial protective immunity in double-transgenic HLA-A2/HER2 mice with self-immune tolerance to HER2. Here, we constructed an adenoviral vector AdVHuRt expressing HuRt fusion protein composed of NH2-HER21-407 (Hu) and COOH-neu408-690 (Rt) fragments, and developed a heterologous human/rat HER2-specific exosome-targeted T-cell vaccine HuRt-TEXO using polyclonal CD4+ T-cells uptaking exosomes released by AdVHuRt-transfected dendritic cells. We found that the HuRt-TEXO vaccine stimulates enhanced CD4+ T-cell responses leading to increased induction of HER2-specific antibody (∼70 µg/ml) compared to that (∼40 µg/ml) triggered by the homologous HER2-TEXO vaccine. By using PE-H-2Kd/HER223-71 tetramer, we determined that HuRt-TEXO stimulates stronger HER2-specific CD8+ T-cell responses eradicating 90% of HER2-specific target cells, while HER2-TEXO-induced CD8+ T-cell responses only eliminating 53% targets. Furthermore, HuRt-TEXO, but not HER2-TEXO vaccination, is capable of suppressing early stage-established HER2-expressing 4T1HER2 breast cancer in its lung metastasis or subcutaneous form in BALB/c mice, and of completely protecting transgenic HLA-A2/HER2 mice from growth of HLA-A2/HER2-expressing BL6-10A2/HER2 melanoma. HuRt-TEXO-stimulated HER2-specific CD8+ T-cells not only are cytolytic to trastuzumab-resistant HLA-A2/HER2-expressing BT474/A2 breast tumor cells in vitro but also eradicates pre-established BT474/A2 tumors in athymic nude mice. Therefore, our novel heterologous human/rat HER2-specific T-cell vaccine HuRt-TEXO, circumventing HER2 tolerance, may provide a new therapeutic alternative for patients with trastuzumab-resistant HER2+ breast tumor.

Human dendritic cells engineered to express alpha tumor necrosis factor maintain cellular maturation and T-cell stimulation capacity.

Dendritic cell (DC) vaccine has been demonstrated to induce antitumor immunity in animal models. It has been shown that the efficiency of antitumor immunity by DC vaccine is closely correlated with DC maturation status. The mature human DCs generated from peripheral blood mononuclear cells (PBMCs) in the presence of granulocyte macrophage-colony-stimulating factor (GM-CSF), interleukin (IL)-4, and tumor necrosis factor (TNF)-alpha have widely contributed to their growing use in cancer vaccination trials. Although the objective clinical immune responses have been observed, the treatment results have proved to be somewhat disappointing. One question of whether these ex vivo-generated mature DCs can maintain their maturation status in vivo after DC vaccination is unclear. In this study, we investigated the influence of different culture media (RPMI 1640/10% fetal calf serum [FCS] versus serum-free AIM-V medium) on DC maturation and the change of maturation status of these ex vivo generated mature DCs during further culturing in medium without inflammatory cytokine TNF-alpha. We previously constructed a recombinant adenovirus AdV-TNF-alpha expressing the transgene human TNF-alpha. We transfected human DCs with AdV-TNF-alpha at multiplicity of infection of 100, resulting in engineered DCs secreting TNF-alpha (4.6 ng/mL/10(6) cells/24 hours). We also conducted kinetic studies to compare the maturation status and the T-cell stimulation capacity by ex vivo-generated mature DCs and TNF-alpha- transgene-engineered DCs during further culturing in medium without TNF-alpha. Our data show that mature DCs can be generated from PBMCs in both Dulbecco's modified Eagle's medium plus 10% FCS and serum-free AIM-V medium containing GM-CSF (100 ng/mL), IL-4 (100 ng/mL), and TNF-alpha (10 ng/mL). However, these mature DCs gradually lost their maturity and became immature ones when culturing in medium in the absence of TNF-alpha. On the contrary, the human DCs engineered to express TNF-alpha can (i) stably maintain their cellular maturation and (ii) efficiently stimulate T-cell proliferation even during culturing ex vivo in medium without TNF-alpha stimulation. Therefore, DCs engineered to express TNF-alpha may also maintain their maturation status and induce more efficient antitumor immune responses when applied in vivo for vaccination. Thus, our results may be important in designing DC-based cancer vaccines in the future.

HER2-directed therapy: current treatment options for HER2-positive breast cancer.

Over the past decade, the management of HER2-positive breast cancer has evolved dramatically. In addition to advances in screening, genetic testing, imaging, surgical and radiation techniques, innovations in medical therapy including widespread use of HER2-directed therapy in early and advanced breast cancer have revolutionized breast cancer care and changed the natural history of HER2-positive breast cancer. A substantial number of HER2-targeted agents are being developed including monoclonal antibodies, small molecule inhibitors, and antibody drug conjugates. Trastuzumab is the prototype HER2-directed therapy that was introduced in the late 1990s for the management of metastatic breast cancer and later showed efficacy in early stage disease. Despite the practice changing impact of trastuzumab and improvement in outcomes of women with HER2-positive breast cancer resistance to trrastuzumab is a major clinical issue, occurring in both early stage and advanced disease, and new treatment strategies are clearly required. Combining HER2-targeted agents and dual HER2 blockade has been successful in early and advanced breast cancer. Furthermore, selected delivery of potent chemotherapeutic agent coupled with HER2 inhibition promises new treatment options. This review is focused on current HER2-directed treatments for women with HER2-positive breast cancer including monoclonal antibodies, small molecule inhibitors, and antibody drug conjugates.

Extrapulmonary small cell cancer: a Canadian province's experience.

BACKGROUND: The objective of this study was to determine variables that correlate with the survival of patients with extrapulmonary small cell carcinoma (EPSCC). METHODS: Medical records of 101 eligible patients with EPSCC who were diagnosed in Saskatchewan from 1971 to 2002 were reviewed. Survival was calculated by using the Kaplan-Meier method. A logistic regression analysis with a backward elimination was carried out to determine prognostic variables that predicted mortality. RESULTS: The median patient age was 72 years (range, 24-100 years), and the male-to-female ratio was 1.4:1. The primary disease sites were as follows: breast, 9%; gastrointestinal, 20%; genitourinary, 18%; gynecologic, 11%; head and neck, 10%; thymus, 2%; and unknown primary site, 31%. Fifty-one patients had limited disease (LD), and 50 patients had extensive disease (ED). Patients with LD had a median overall survival of 34 months (range, 0.2-276 months) compared with 2 months (range, 0.1-108 months) in patients with ED (P < .0001). Among different primary sites, patients with gynecologic small cell cancer (SCC) had a median survival of 54.4 months, whereas patients with SCC of an unknown primary site had a survival of 2.5 months. Among various variables that were examined with respect to their prognostic importance, an abnormal white blood cell count (odds ratio [OR], 6.9; 95% confidence interval [95% CI], 3.4-14.1), an Eastern Cooperative Oncology Group performance status >2 (OR, 4.5; 95% CI, 2.1-9.9), and ED (OR, 2.7; 95% CI, 1.4-5.0) were found to be correlated significantly with mortality. CONCLUSIONS: The gastrointestinal and genitourinary tracts were the 2 major sites involved by EPSCC in the current series. Survival varied according to the primary sites, and patients with gynecologic tumors had the best prognosis. An abnormal white blood cell count, a poor performance status, and disease extent were important factors in predicting survival.

A new method for measuring inhibition of platelet function by nonsteroidal antiinflammatory drugs.

Aspirin is widely used to help prevent vascular occlusion caused by atherosclerotic vascular disease. We used a platelet-aggregation assay (PAA) to evaluate the reliability of a proprietary platelet agonist, platelet prostaglandin agonist (PPA), to detect the amount of platelet inhibition induced by four different classes of nonsteroidal antiinflammatory drugs (NSAIDs) with antiplatelet effects. Twenty normal donors were evaluated before and 24 hours after ingestion of 325 mg of aspirin. With 125 micromol/L PPA, the slope of the PPA-PAA curve completely differentiated aspirin-treated from normal platelets. The aspirin platelet slope, 27.9 +/- 2.0 (range 5.5-47), was significantly decreased (P <.001) compared with the findings before administration of aspirin, 75 +/- 3.1 (range 50-125). Additionally, the time elapsed before 50% platelet aggregation (T(50)) with aspirin, 10.1 +/- 0.7 minutes (range 4.7-17), was significantly prolonged (P <.05) compared with the mean time before administration of aspirin (4.2 +/- 0.2 minutes, range 1.7-6.4). Aspirin in a daily dosage of 325 mg for 14 days produced significantly greater inhibition of PPA-PAA than that induced by a single 325-mg dose (P <.001). The long-term platelet-inhibitory effects of aspirin in 9 normal volunteers were evaluated with PPA-PAA 2, 8, 24, 48, 72, and 96 hours after a single dose of aspirin, 81 or 325 mg. Compared with the preaspirin slope, 79.6 +/- 1.9, the maximal decrease in slope occurred after 2 hours for both 81 mg (61.3 +/- 6.7) and 325 mg (12.1 +/- 1.8). The decreased slopes and increased T(50) observed at 2, 8, and 24 hours (P <.001) reflected the greater degree of platelet inhibition with 325 mg than with 81 mg aspirin. Inhibition of PPA-PAA was observed with nonaspirin nonsteroidal antiinflammatory drugs (NNSAIDs), but, compared with aspirin, the inhibition was minimal. PPA-PAA may be used to help measure the magnitude of NSAID-induced inhibition of platelets.