Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV.

Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.Leukemia advance online publication, 26 February 2016; doi:10.1038/leu.2016.20.

Natural History of Geographic Atrophy Progression Secondary to Age-Related Macular Degeneration (Geographic Atrophy Progression Study).

PURPOSE The Geographic Atrophy Progression (GAP) study was designed to assess the rate of geographic atrophy (GA) progression and to identify prognostic factors by measuring the enlargement of the atrophic lesions using fundus autofluorescence (FAF) and color fundus photography (CFP). DESIGN Prospective, multicenter, noninterventional natural history study. PARTICIPANTS A total of 603 participants were enrolled in the study; 413 of those had gradable lesion data from FAF or CFP, and 321 had gradable lesion data from both FAF and CFP. METHODS Atrophic lesion areas were measured by FAF and CFP to assess lesion progression over time. Lesion size assessments and best-corrected visual acuity (BCVA) were conducted at screening/baseline (day 0) and at 3 follow-up visits: month 6, month 12, and month 18 (or early exit). MAIN OUTCOME MEASURES The GA lesion progression rate in disease subgroups and mean change from baseline visual acuity. RESULTS Mean (standard error) lesion size changes from baseline, determined by FAF and CFP, respectively, were 0.88 (0.1) and 0.78 (0.1) mm(2) at 6 months, 1.85 (0.1) and 1.57 (0.1) mm(2) at 12 months, and 3.14 (0.4) and 3.17 (0.5) mm(2) at 18 months. The mean change in lesion size from baseline to month 12 was significantly greater in participants who had eyes with multifocal atrophic spots compared with those with unifocal spots (P < 0.001) and those with extrafoveal lesions compared with those with foveal lesions (P = 0.001). The mean (standard deviation) decrease in visual acuity was 6.2 ± 15.6 letters for patients with image data available. Atrophic lesions with a diffuse (mean 0.95 mm(2)) or banded (mean 1.01 mm(2)) FAF pattern grew more rapidly by month 6 compared with those with the "none" (mean, 0.13 mm(2)) and focal (mean, 0.36 mm(2)) FAF patterns. CONCLUSIONS Although differences were observed in mean lesion size measurements using FAF imaging compared with CFP, the measurements were highly correlated with one another. Significant differences were found in lesion progression rates in participants stratified by hyperfluorescence pattern subtype. This large GA natural history study provides a strong foundation for future clinical trials.

Secondary left ventricular ejection fraction response to beta blocker therapy in heart failure patients

Chronic β-blocker treatment improves survival and left ventricular ejection fraction (LVEF) in patients with systolic heart failure (HF). Data on whether the improvement in LVEF after β-blocker therapy is sustained for a long term or whether there is a loss in LVEF after an initial gain is not known. Our study sought to determine the prevalence and prognostic role of secondary decline in LVEF in chronic systolic HF patients on β-blocker therapy and characterize these patients. Retrospective chart review of HF hospitalizations fulfilling Framingham Criteria was performed at the MEDVAMC between April 2000 and June 2006. Follow up vital status and recurrent hospitalizations were ascertained until May 2010. Three groups of patients were identified based on LVEF response to beta blockers; group A with secondary decline in LVEF following an initial increase, group B with progressive increase in LVEF and group C with progressive decline in LVEF. Covariate adjusted Cox proportional hazard models were used to examine differences in heart failure re-hospitalizations and all cause mortality between the groups. Twenty five percent (n=27) of patients had a secondary decline in LVEF following an initial gain. The baseline, peak and final LVEF in this group were 27.6±12%, 40.1±14% and 27.4±13% respectively. The mean nadir LVEF after decline was 27.4±13% and this decline occurred at a mean interval of 2.8±1.9 years from the day of beta blocker initiation. These patients were older, more likely to be whites, had advanced heart failure (NYHA class III/IV) more due to a non ischemic etiology compared to groups B & C. They were also more likely to be treated with metoprolol (p=0.03) compared to the other two groups. No significant differences were observed in combined risk of all cause mortality and HF re-hospitalization [hazard ratio 0.80, 95% CI 0.47 to 1.38, p=0.42]. No significant difference was observed in survival estimates between the groups. In conclusion, a late decline in LVEF does occur in a significant proportion of heart failure patients treated with beta blockers, more so in patients treated with metoprolol.^

FEMALE SEXUAL MATURATION AND BLOOD PRESSURE (SECONDARY-SEX CHARACTERISTICS, GROWTH, DEVELOPMENT)

This study described the relationship of sexual maturation and blood pressure in a sample (n = 361) of white females, ages seven through 18, attending public schools in a defined area of Central Texas during October through December, 1984. Other correlates of blood pressure were also described for this sample.^ A survey was performed to obtain the data on height, weight, body mass, pulse rate, upper arm circumference and length, and blood pressure. Each subject self-assessed her secondary sex characteristics (breast and pubic hair) according to drawings of the Tanner stages of maturation. The subjects were interviewed to obtain data on personal health habits and menstrual status. Student age, ethnic group and place of residence were abstracted from school records. Parents or guardians of the subjects responded to a questionnaire pertaining to parental and subject health history and parents' occupation and educational attainment.^ In the simple linear regression analysis, sexual maturation and variables of body size were significantly (p < 0.001) and positively associated with systolic and fourth- and fifth-phase diastolic blood pressure. The demographic and socioeconomic variables were not sufficiently variant in this population to have differential effects on the relation between blood pressure and maturation. Stepwise multiple regression was used to assess the contribution of sexual maturation to the variance of blood pressure after accounting for the variables of body size. Sexual maturation (breast stage) along with weight, height and body mass remained in the multiple regression models for fourth- and fifth-phase diastolic blood pressure. Only height and body mass remained in the regression model for systolic blood pressure; sexual maturation did not contribute more to the explanation of the systolic blood pressure variance.^ The association of sexual maturation with blood pressure level was established in this sample of young white females. More research is needed first, to determine if this relationship prevails in other populations of young females, and second, to determine the relationship of sexual maturation sequence and change with the change of blood pressure during childhood and adolescence. ^

Pre-pregnancy obesity on the border and pregnancy complications: A secondary analysis comparing post-natal adult women in Matamoros, Mexico and Cameron County, Texas

Obesity during pregnancy is a serious health concern which has been associated with many adverse health outcomes for both the mother and the infant. In addition, data on the prevalence of obesity and its effects on pregnant women living in the border region are limited. This goal of this study was to examine the prevalence of preconception obesity among women living on each side of the Brownsville-Matamoros border who have just given birth, the relationship between obesity and pregnancy complications for the total population, and these associations by location. Study participants were drawn from a sample (n=947) from the Brownsville-Matamoros Sister City Project which included women from 10 border region hospitals (6 in Matamoros, 4 in Cameron County) who were recruited based on hospital log records indicating they had given birth to a live infant. De-identified data from verbal questionnaires administered within twenty-four hours after birth were analyzed to determine prevalence of preconception obesity on both sides of the border, and associated pregnancy outcomes for women residing in the United States and those in Mexico. Participants with missing height or weight data were excluded from analyses in this study, resulting in a final sample of 727 women. Significant associations were found between pre-pregnancy obesity and adverse pregnancy outcomes (OR=1.85, CI=1.30–2.64), hypertensive conditions (OR=2.76, CI=1.72–4.43), and macrosomia (OR=6.77, CI=1.13–40.57) using the total sample. Comparisons between the United States and Mexico sides of the border showed differences; associations between preconception obesity and adverse pregnancy outcomes were marginally significant among women in the United States (p=0.05), but failed to reach significance within this group for each individual complication. However, significant associations were found between obesity and preeclampsia (OR=3.61, CI=2.14–6.10), as well as obesity and the presence of one or more adverse pregnancy outcome (OR=2.29, CI=1.30–4.02), among women in Mexico. The results from this analysis provide new information specific to women on the Texas and Mexico border, a region that had not previously been studied. These significant associations between preconception obesity and adverse birth outcomes indicate that efforts to prevent obesity should focus on women of childbearing age, especially in Mexico.^

Influenza vaccination as a primary or secondary prevention for cardiovascular diseases: A systematic review of the literature

Background: Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide. CVD mainly comprise of coronary heart disease and stroke and were ranked first and fourth respectively amongst leading causes of death in the United States. Influenza (flu) causes annual outbreaks and pandemics and is increasingly recognized as an important trigger for acute coronary syndromes and stroke. Influenza vaccination is an inexpensive and effective strategy for prevention of influenza related complications in high risk individuals. Though it is recommended for all CVD patients, Influenza vaccine is still used at suboptimal levels in these patients owing to prevailing controversy related to its effectiveness in preventing CVD. This review was undertaken to critically assess the effectiveness of influenza vaccination as a primary or secondary prevention method for CVD. ^ Methods: A systematic review was conducted using electronic databases OVID MEDLINE, PUBMED (National Library of Medicine), EMBASE, GOOGLE SCHOLAR and TRIP (Turning Research into Practice). The study search was limited to peer-reviewed articles published in English language from January 1970 through May 2012. The case control studies, cohort studies and randomized controlled trials related to influenza vaccination and CVD, with data on at least one of the outcomes were identified. In the review, only population-based epidemiologic studies in all ethnic groups and of either sex and with age limitation of 30 yrs or above, with clinical CVD outcomes of interest were included. ^ Results: Of the 16 studies (8 case control studies, 6 cohort studies and 2 randomized controlled trials) that met the inclusion criteria, 14 studies reported that there was a significant benefit in u influenza vaccination as primary or secondary prevention method for preventing new cardiovascular events. In contrary to the above findings, two studies mentioned that there was no significant benefit of vaccination in CVD prevention. ^ Conclusion: The available body of evidence in the review elucidates that vaccination against influenza is associated with reduction in the risk of new CVD events, hospitalization for coronary heart disease and stroke and as well as the risk of death. The study findings disclose that the influenza vaccination is very effective in CVD prevention and should be encouraged for the high risk population. However, larger and more future studies like randomized control trials are needed to further evaluate and confirm these findings. ^

Application of the general linear model to assess the effect of missing data on bone marrow mononuclear cell therapy with infusion timing and follow-up MRI

With most clinical trials, missing data presents a statistical problem in evaluating a treatment's efficacy. There are many methods commonly used to assess missing data; however, these methods leave room for bias to enter the study. This thesis was a secondary analysis on data taken from TIME, a phase 2 randomized clinical trial conducted to evaluate the safety and effect of the administration timing of bone marrow mononuclear cells (BMMNC) for subjects with acute myocardial infarction (AMI).^ We evaluated the effect of missing data by comparing the variance inflation factor (VIF) of the effect of therapy between all subjects and only subjects with complete data. Through the general linear model, an unbiased solution was made for the VIF of the treatment's efficacy using the weighted least squares method to incorporate missing data. Two groups were identified from the TIME data: 1) all subjects and 2) subjects with complete data (baseline and follow-up measurements). After the general solution was found for the VIF, it was migrated Excel 2010 to evaluate data from TIME. The resulting numerical value from the two groups was compared to assess the effect of missing data.^ The VIF values from the TIME study were considerably less in the group with missing data. By design, we varied the correlation factor in order to evaluate the VIFs of both groups. As the correlation factor increased, the VIF values increased at a faster rate in the group with only complete data. Furthermore, while varying the correlation factor, the number of subjects with missing data was also varied to see how missing data affects the VIF. When subjects with only baseline data was increased, we saw a significant rate increase in VIF values in the group with only complete data while the group with missing data saw a steady and consistent increase in the VIF. The same was seen when we varied the group with follow-up only data. This essentially showed that the VIFs steadily increased when missing data is not ignored. When missing data is ignored as with our comparison group, the VIF values sharply increase as correlation increases.^

Experimental growth characteristics, cell size, yessotoxin values and bioassay data of Protoceratium reticulatum (Dinophyceae)

Harmful algal blooms are mainly caused by marine dinoflagellates and are known to produce potent toxins that may affect the ecosystem, human activities and health. Such events have increased in frequency and intensity worldwide in the past decades. Numerous processes involved in Global Change are amplified in the Arctic, but little is known about species specific responses of arctic dinoflagellates. The aim of this work was to perform an exhaustive morphological, phylogenetical and toxinological characterization of Greenland Protoceratium reticulatum and, in addition, to test the effect of temperature on growth and production of bioactive secondary metabolites. Seven clonal isolates, the first isolates of P. reticulatum available from arctic waters, were phylogenetically characterized by analysis of the LSU rDNA. Six isolates were further characterized morphologically and were shown to produce both yessotoxins (YTX) and lytic compounds, representing the first report of allelochemical activity in P. reticulatum. As shown for one of the isolates, growth was strongly affected by temperature with a maximum growth rate at 15 °C, a significant but slow growth at 1 °C, and cell death at 25 °C, suggesting an adaptation of P. reticulatum to temperate waters. Temperature had no major effect on total YTX cell quota or lytic activity but both were affected by the growth phase with a significant increase at stationary phase. A comparison of six isolates at a fixed temperature of 10 °C showed high intraspecific variability for all three physiological parameters tested. Growth rate varied from 0.06 to 0.19 per day, and total YTX concentration ranged from 0.3 to 15.0 pg YTX/cell and from 0.5 to 31.0 pg YTX/cell at exponential and stationary phase, respectively. All six isolates performed lytic activity; however, for two isolates lytic activity was only detectable at higher cell densities in stationary phase.

Geochemical analyses of secondary minerals from ODP Leg 115 basalts (Tables 1+2)

Basalts recovered along the Reunion hotspot track on Ocean Drilling Program (ODP) Leg 115 range in age from 34 Ma at Site 706 to 64 Ma at Site 707. They have undergone various degrees of secondary alteration. Within single holes the amount of alteration can vary from a few percent to near complete replacement of phenocrysts and groundmass by secondary minerals. Olivine appears to be the most susceptible to alteration and in some sections it is the only mineral altered. In other sections, olivine, pyroxene and plagioclase phenocrysts, and groundmass have been completely replaced by secondary minerals. Clays are the predominant form of secondary mineralization. In addition to replacing olivine, pyroxene, glass, and groundmass, clays have filled veins, vesicles, and voids. Minor amounts of calcite, zeolites, and K-feldspar were also detected. The clays that filled vesicles and veins often show color zonations of dark, opaque bands near the edges that grade into tan or green transparent regions in the centers of the veins. The electron microprobe was used to obtain chemical analyses of these veins as well as to characterize isolated clays that replaced specific minerals and filled voids and vesicles.

(Table 2) Mineralogy and carbon, oxygen, and hydrogen isotope ratios for secondary mineral samples from igneous rocks from ODP Hole 128-794D

The basaltic rocks of Hole 794D drilled during Leg 128 are strongly altered. Microprobe analyses and XRD spectra on small quantities of matter extracted from thin sections show that primary minerals and glassy zones of the groundmass are totally or partially replaced by clay minerals with chlorite/saponite mixed-layer composition whatever the rock sample considered. This mixed-layer was also identified in veins and vesicles where it crystallizes in spheroidal aggregates. The largest veins and vesicles are filled by a zoned deposit: the chlorite/saponite mixed-layer always occupies the central part and is rimmed by pure saponite. Calcite crystallizes in secondary fractures which crosscut the clayey veins and vesicles. Chemographic analysis based on the M+-4Si-3R2+ projection shows that the chemical composition of the saponite component in the mixed-layer is identical to that of the free saponite. This indicates that the clay mineral crystallization was controlled by the chemical composition of the alteration fluids. From petrographic evidence, it is suggested that both chlorite/saponite mixed-layer and free saponite belong to the same hydrothermal event and are produced by a temperature decrease. This is supported by the stable isotopic data. The isotopic data show very little variation: d18O saponite ranges from 13.1 per mil to 13.5 per mil, and dD saponite from -73.6 per mil to -70.0 per mil. d18O calcite varies from +19.7 per mil to +21.9 per mil vs SMOW and d13C from -3.2 per mil to +0.4 per mil vs. PDB. These values are consistent with seawater alteration of the basalt. The formation of saponite took place at 150°-180°C and the formation of calcite at about 65°C.