Early prenatal use of a multivitamin diminishes the risk for inadequate vitamin D status in pregnant women: results from the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort study.

BACKGROUND: Reports on the adequacy of vitamin D status of pregnant women are not available in Canada. OBJECTIVES: The objectives of this study were to examine vitamin D status across pregnancy and identify the correlates of vitamin D status of pregnant women in Canada. METHODS: Pregnant women (≥18 years) from 6 provinces (2008-2011) participating in a longitudinal cohort were studied. Sociodemographic data, obstetrical histories, and dietary and supplemental vitamin D intakes were surveyed. Plasma 25-hydroxyvitamin D (25OHD) was measured using an immunoassay standardized to LC-MS/MS from samples collected during the first (n = 1905) and third trimesters (n = 1649) and at delivery (n = 1543). The proportion of women with ≥40 nmol/L of plasma 25OHD (adequate status) was estimated at each time point, and factors related to achieving this cut point were identified using repeated-measures logistic regression. Differences in 25OHD concentrations across trimesters and at delivery were tested a using repeated-measures ANOVA with a post hoc Tukey's test. RESULTS: In the first trimester, 93.4% (95% CI: 92.3%-94.5%) of participants had 25OHD ≥40 nmol/L. The mean plasma 25OHD concentration increased from the first to the third trimester and then declined by delivery (69.8 ± 0.5 nmol/L, 78.6 ± 0.7 nmol/L, and 75.7 ± 0.7 nmol/L, respectively; P < 0.0001). A lack of multivitamin use early in pregnancy reduced the odds of achieving 25OHD ≥40 nmol/L (ORadj = 0.33; 95% CI: 0.25-0.42) across all time points. Factors associated with not using a prenatal multivitamin included multiparity (ORadj = 2.08; 95% CI: 1.42-3.02) and a below-median income (ORadj = 1.39; 95% CI: 1.02-1.89). CONCLUSIONS: The results from this cohort demonstrate the importance of early multivitamin supplement use to achieve an adequate vitamin D status in pregnant women.

Comparison of Electronic Versus Manual Mass-Casualty Incident Triage.

IntroductionMass-casualty incidents (MCIs) easily overwhelm a health care facility's human and material resources through the extraordinary influx of casualties. Efficient and accurate triage of incoming casualties is a critical step in the hospital disaster response.Hypothesis/ProblemTraditionally, triage during MCIs has been manually performed using paper cards. This study investigated the use of electronic Simple Triage and Rapid Treatment (START) triage as compared to the manual method. METHODS: This observational, crossover study was performed during a live MCI simulation at an urban, Canadian, Level 1 trauma center on May 26, 2016. Health care providers (two medical doctors [MDs], two paramedics [PMs], and two registered nurses [RNs]) each triaged a total of 30 simulated patients - 15 by manual (paper-based) and 15 by electronic (computer-based) START triage. Accuracy of triage categories and time of triage were analyzed. Post-simulation, patients and participating health care providers also completed a feedback form. RESULTS: There was no difference in accuracy of triage between the electronic and manual methods overall, 83% and 80% (P=1.0), between providers or between triage categories. On average, triage time using the manual method was estimated to be 8.4 seconds faster (P<.001) for PMs; and while small differences in triage times were observed for MDs and RNs, they were not significant. Data from the participant feedback survey showed that the electronic method was preferred by most health care providers. Patients had no preference for either method. However, patients perceived the computer-based method as "less personal" than the manual triage method, but they also perceived the former as "better organized." CONCLUSION: Hospital-based electronic START triage had the same accuracy as hospital-based manual START triage, regardless of triage provider type or acuity of patient presentations. Time of triage results suggest that speed may be related to provider familiarity with a modality rather than the modality itself. Finally, according to patient and provider perceptions, electronic triage is a feasible modality for hospital triage of mass casualties. Further studies are required to assess the performance of electronic hospital triage, in the context of a rapid surge of patients, and should consider additional efficiencies built in to electronic triage systems. This study presents a framework for assessing the accuracy, triage time, and feasibility of digital technologies in live simulation training or actual MCIs. BolducC, MaghrabyN, FokP, LuongTM, HomierV. Comparison of electronic versus manual mass-casualty incident triage. Prehosp Disaster Med. 2018;33(3):273-278.

NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells.

Tumor infiltration with effector CD8(+) T cells (T(eff)) predicts longer recurrence-free survival in many types of human cancer, illustrating the broad significance of T(eff) for effective immunosurveillance. Colorectal tumors with reduced accumulation of T(eff) express low levels of T(eff)-attracting chemokines such as CXCL10/IP10 and CCL5/RANTES. In this study, we investigated the feasibility of enhancing tumor production of T(eff)-attracting chemokines as a cancer therapeutic strategy using a tissue explant culture system to analyze chemokine induction in intact tumor tissues. In different tumor explants, we observed highly heterogeneous responses to IFNα or poly-I:C (a TLR3 ligand) when they were applied individually. In contrast, a combination of IFNα and poly-I:C uniformly enhanced the production of CXCL10 and CCL5 in all tumor lesions. Moreover, these effects could be optimized by the further addition of COX inhibitors. Applying this triple combination also uniformly suppressed the production of CCL22/MDC, a chemokine associated with infiltration of T regulatory cells (T(reg)). The T(eff)-enhancing effects of this treatment occurred selectively in tumor tissues, as compared with tissues derived from tumor margins. These effects relied on the increased propensity of tumor-associated cells (mostly fibroblasts and infiltrating inflammatory cells) to hyperactivate NF-κB and produce T(eff)-attracting chemokines in response to treatment, resulting in an enhanced ability of the treated tumors to attract T(eff) cells and reduced ability to attract T(reg) cells. Together, our findings suggest the feasibility of exploiting NF-κB hyperactivation in the tumor microenvironment to selectively enhance T(eff) entry into colon tumors.

Fludarabine and cytarabine in patients with acute myeloid leukemia refractory to two different courses of front-line chemotherapy.

The most effective regimen for acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after two different courses of front-line chemotherapy has not been established. We therefore evaluated the efficacy, toxicity, and prognostic factors for achieving CR following treatment with fludarabine and cytarabine in 25 newly diagnosed AML patients who did not respond to initial therapy with idarubicin and cytarabine followed by mitoxantrone and etoposide. CR was achieved in 32% of patients; in 55% of patients with intermediate-risk karyotype and in 14% with unfavorable-risk. Eight percent died of infectious complications. Median duration of overall survival was 6.6 months (95% CI 3.4 months to ∞); 3.4 months (95% CI 0.8-8.6 months) for patients with an unfavorable-risk karyotype and 18.1 months (95% CI 5.0 months to ∞) with an intermediate-risk karyotype (p=0.02). Our data suggest that poor-risk karyotype patients are unlikely to benefit from third course treatment with fludarabine-cytarabine, and that this regimen merits further investigation in AML patients with good or intermediate-risk karyotype that have persistent leukemia after two courses of front-line chemotherapy.

Gemtuzumab ozogamicin as first-line treatment in patients aged 70 years or older with acute myeloid leukemia.

BACKGROUND: Elderly patients with acute myeloid leukemia (AML) are generally unable to withstand the rigors of intensive induction chemotherapy and its attendant complications. Gemtuzumab ozogamicin (GO) is an immunoconjugate that had demonstrated activity in recurrent AML. METHODS: The objective of the current study was to determine the prognostic factors for achievement of complete remission (CR) in newly diagnosed elderly AML patients treated with GO as initial induction therapy. A retrospective study was performed of efficacy and toxicity associated with GO therapy, and factors potentially predictive of response were assessed in 49 previously untreated AML patients. RESULTS: CR was achieved in 14% of all treated patients. Among the patients with an intermediate-risk karyotype, the CR rate was 30%, compared with none with an unfavorable karyotype. The median duration of overall survival was 3.7 months (95% confidence interval [95% CI], 1.4-6.9 months), and the median recurrence-free survival in patients who achieved CR was 11.8 months (95% CI, 5.0-ind months). CONCLUSIONS: These data suggest that GO should be considered as a first-line treatment option in older patients with AML with intermediate-risk cytogenetics who cannot tolerate high-dose induction chemotherapy.

Complementary prognostic values of ST segment deviation and Thrombolysis In Myocardial Infarction (TIMI) risk score in non-ST elevation acute coronary syndromes: Insights from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study.

BACKGROUND: Although the Thrombolysis In Myocardial Infarction (TIMI) score incorporates ST deviation, it does not account for characteristics of the ST deviations. In the present study, it was hypothesized that the magnitude and characteristics of ST deviation may add to the prognostic values of the TIMI risk score in acute coronary syndrome (ACS) patients, particularly in lower-risk patients with a TIMI risk score of less than 5. OBJECTIVE: To evaluate the prognostic value of combining the TIMI risk score and characteristics of ST deviation in patients with non-ST elevation ACS and a TIMI risk score of less than 5. METHODS: The death/myocardial infarction (MI) rates of 1296 patients enrolled in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) angiographic substudy were examined. RESULTS: Patients without a TIMI risk score of 5 or greater, and without an ST deviation of 1 mm or greater had the lowest six-month rate of death/ MI (5%). In patients with a TIMI risk score of less than 5, the six-month death/MI rate was increased in those with ST depression of 2 mm or greater compared with patients with a similar TIMI risk score and without ST deviation of 1 mm or greater (24% versus 5%, P<0.001). The presence of ST deviation of 2 mm or greater identified an additional 15% of patients with an increased six-month death/MI rate in patients with a TIMI risk score of less than 5. CONCLUSION: ST segment deviation of 2 mm or greater confers additional prognostic information in non-ST elevation ACS patients with a TIMI risk score of less than 5. Patients with a TIMI risk score of less than 5 and ST deviation of 2 mm or less had the lowest risk of six-month death/MI.

Mitoxantrone and etoposide in patients with newly diagnosed acute myeloid leukemia with persistent leukemia after a course of therapy with cytarabine and idarubicin.

The most effective regimen for patients with acute myeloid leukemia (AML) who do not achieve complete remission (CR) after one course of cytarabine and an anthracycline has not been extensively studied. We evaluated retrospectively the efficacy, toxicity, and prognostic factors for the achievement of CR following mitoxantrone and etoposide in 74 patients with newly diagnosed AML who did not respond to one course of therapy with cytarabine and idarubicin. CR was achieved in 39% of patients; 14% died of infectious complications; no grade 3 or 4 hepatic toxicities were observed. Median duration of overall survival was 9.0 months (95% CI 5.8-14.9 months). The median duration of relapse-free survival was 11.0 months (95% CI: 9.0-19.3 months). A lower CR rate was associated with unfavorable risk status at diagnosis and higher percent blasts. Our data suggest that the combination of etoposide and mitoxantrone is an effective second-course therapy in patients with newly diagnosed AML.

A new generalization of Weibull distribution with application to a breast cancer data set.

In this article, we propose a new generalization of the Weibull distribution, which incorporates the exponentiated Weibull distribution introduced by Mudholkar and Srivastava (IEEE Trans. Reliab. 1993; 42:299-302) as a special case. We refer to the new family of distributions as the beta-Weibull distribution. We investigate the potential usefulness of the beta-Weibull distribution for modeling censored survival data from biomedical studies. Several other generalizations of the standard two-parameter Weibull distribution are compared with regards to maximum likelihood inference of the cumulative incidence function, under the setting of competing risks. These Weibull-based parametric models are fit to a breast cancer data set from the National Surgical Adjuvant Breast and Bowel Project. In terms of statistical significance of the treatment effect and model adequacy, all generalized models lead to similar conclusions, suggesting that the beta-Weibull family is a reasonable candidate for modeling survival data.

Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma.

PURPOSE: Radioimmunotherapy has been approved for relapsed follicular lymphoma (FL), including rituximab-refractory FL. This study was designed to determine the CR rate with short-course chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) followed by 90-Y ibritumomab tiuxetan (RIT) with extended rituximab as first-line treatment. EXPERIMENTAL DESIGN: Between March 2004 and February 2007, 60 patients with stage II to IV symptomatic or bulky FL from a single institution supported by a large community network entered this phase II trial. Patients received CHOP-R for three treatment cycles before RIT followed by four additional weekly treatments with rituximab. Response was determined using fusion [(18) F] fluorodeoxyglucose-positron emission tomography (PET)-computed tomography (CT) imaging. RESULTS: Of the 60 patients entering this trial, 55 patients completed all protocol therapy. The median follow up was 19.7 months (range, 0.26-35.9 months). For intent-to-treat analysis, the complete response (CR) rate after CHOP-R, as assessed by CT and PET imaging, was 40% and 46%, respectively. After RIT, the CR rate improved, as assessed by CT and PET imaging, to 82% and 89%, respectively. Ten patients have progressed, including eight from best response of CR. Seven of 18 patients who were PET positive after CHOP-R progressed compared with 3 of 37 patients who were PET negative (P=0.010). CONCLUSIONS: In patients with previously untreated, symptomatic or bulky FL, short-course chemoimmunotherapy and consolidation RIT and extended rituximab resulted in a high CR rate. Failure to achieve an early PET CR after CHOP-R indicated high risk of relapse.

Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis.

The hepatocyte growth factor (HGF)/c-Met signaling pathway is involved in lung tumor growth and progression, and agents that target this pathway have clinical potential for lung cancer treatment. L2G7, a single potent anti-human HGF neutralizing monoclonal antibody, showed profound inhibition of human HGF-induced phosphorylated mitogen-activated protein kinase induction, wound healing, and invasion in lung tumor cells in vitro. Transgenic mice that overexpress human HGF in the airways were used to study the therapeutic efficacy of L2G7 for lung cancer prevention. Mice were treated with the tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, over 4 weeks. Beginning at week 3, i.p. treatment with 100 mug L2G7 or isotype-matched antibody control, 5G8, was initiated and continued through week 15. The mean number of tumors per mouse in the L2G7-treated group was significantly lower than in the control group (1.58 versus 3.19; P = 0.0005). Proliferative index was decreased by 48% (P = 0.013) in tumors from L2G7-treated mice versus 5G8-treated mice, whereas extent of apoptosis was increased in these same tumors by 5-fold (P = 0.0013). Phosphorylated mitogen-activated protein kinase expression was also significantly decreased by 84% in tumors from L2G7-treated mice versus 5G8-treated mice (P = 0.0003). Tumors that arose in HGF transgenic animals despite L2G7 treatment were more likely to contain mutant K-ras, suggesting that targeting the HGF/c-Met pathway may not be as effective if downstream signaling is activated by a K-ras mutation. These preclinical results show that blocking the HGF/c-Met interaction with a single monoclonal antibody delivered systemically can have profound inhibitory effects on development of lung tumors.

Serum biomarker profiles and response to neoadjuvant chemotherapy for locally advanced breast cancer.

INTRODUCTION: Neoadjuvant chemotherapy has become the standard of care for the diverse population of women diagnosed with locally advanced breast cancer. Serum biomarker levels are increasingly being investigated for their ability to predict therapy response and aid in the development of individualized treatment regimens. Multianalyte profiles may offer greater predictive power for neoadjuvant treatment response than the individual biomarkers currently in use. METHODS: Serum samples were collected from 44 patients enrolled in a phase I-II, open-label study of liposomal doxorubicin and paclitaxel in combination with whole breast hyperthermia for the neoadjuvant treatment of locally advanced breast cancer (stage IIB or stage III). Samples were collected prior to each of four rounds of treatment and prior to definitive surgery. Samples were assayed by Luminex assay for 55 serum biomarkers, including cancer antigens, growth/angiogenic factors, apoptosis-related molecules, metastasis-related molecules, adhesion molecules, adipokines, cytokines, chemokines, hormones, and other proteins. RESULTS: Biomarker levels were compared retrospectively with clinical and pathologic treatment responses. Univariate analysis of the data identified several groups of biomarkers that differed significantly among treatment outcome groups early in the course of neoadjuvant chemotherapy. Multivariate statistical analysis revealed multibiomarker panels that could differentiate between treatment response groups with high sensitivity and specificity. CONCLUSION: We demonstrate here that serum biomarker profiles may offer predictive power concerning treatment response and outcome in the neoadjuvant setting. The continued development of these findings will be of considerable clinical utility in the design of treatment regimens for individual breast cancer patients. TRIAL REGISTRATION: #NCT00346229.

Prognostic significance of blood markers of inflammation in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty and effects of pexelizumab, a C5 inhibitor: a substudy of the COMMA trial.

AIMS: Pexelizumab, a monoclonal antibody inhibiting C5, reduced 90 day mortality and shock in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial without apparent reductions in infarct size. Inflammation is a critical component of ST-elevation myocardial infarction (STEMI); this substudy examines prognostic values of selected markers and treatment effects. METHODS AND RESULTS: C-reactive protein, interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha) serum levels were assessed in 337 patients enrolled in either the placebo or the pexelizumab 24 h infusion group. Higher C-reactive protein and IL-6 levels at baseline, 24 h, and 72 h were strongly associated with increased subsequent death (P<0.002 at baseline and 24 h, P<0.02 at 72 h); and all baseline marker levels with death or cardiogenic shock (P<0.03) within 90 days. C-reactive protein and IL-6 levels were similar at baseline, but significantly lower 24 h later with pexelizumab, when compared with placebo (17.1 vs. 25.5 mg/L, P=0.03 and 51.0 vs. 63.8 pg/mL, P=0.04, respectively). At 72 h, corresponding levels were similar, whereas TNF-alpha was slightly higher (P=0.04) in the treated group. CONCLUSION: Inflammation markers and their serial changes predict death and shock in patients with STEMI undergoing primary angioplasty. Pexelizumab reduced C-reactive protein and IL-6, suggesting treatment benefits mediated through anti-inflammatory effects.