Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance: a population-based study

Background

There are limited data on survival patterns among patients with monoclonal gammopathy of undetermined significance.

Design and Methods

We compared the survival of 4,259 patients with monoclonal gammopathy of undetermined significance, collected from hematology outpatient units in Sweden, with the survival of the general population by computing relative survival ratios. We also compared causes of death in these patients with those in 16,151 matched controls.

Results

One-, 5-, 10-, and 15-year relative survival ratios were 0.98 (95% CI 0.97–0.99), 0.93 (0.91–0.95), 0.82 (0.79–0.84), and 0.70 (0.64–0.76), respectively. Younger age at diagnosis of the gammopathy was associated with a significantly lower excess mortality compared to that in older patients (p<0.001). The excess mortality among patients with gammopathy increased with longer follow-up (p<0.0001). IgM (versus IgG/A) gammopathy was associated with a superior survival (p=0.038). Patients with monoclonal gammopathy of undetermined significance had an increased risk of dying from multiple myeloma (hazards ratio (HR)=553; 95% CI 77–3946), Waldenström’s macroglobulinemia (HR=∞), other lymphoproliferative malignancies (6.5; 2.8–15.1), other hematologic malignancies (22.9; 8.9–58.7), amyloidosis (HR=∞), bacterial infections (3.4; 1.7–6.7), ischemic heart disease (1.3; 1.1–1.4), other heart disorders (1.5; 1.2–1.8), other hematologic conditions (6.9; 2.7–18), liver (2.1; 1.1–4.2), and renal diseases (3.2; 2.0–4.9).

Conclusions

Our finding of decreased life expectancy in patients with monoclonal gammopathy of undetermined significance, which was most pronounced in the elderly and explained by both malignant transformation and non-malignant causes, is of importance in the understanding and clinical management of this disease. The underlying mechanisms may be causally related to the gammopathy, but may also be explained by underlying disease that led to the detection of the hematologic disease. Our results are of importance since they give a true estimation of survival in patients with monoclonal gammopathy of undetermined significance diagnosed in clinical practice.     

The antimicrobial peptide, lactoferricin B, is cytotoxic to neuroblastoma cells in vitro and inhibits xenograft growth in vivo

Antimicrobial peptides have been shown to exert cytotoxic activity towards cancer cells through their ability to interact with negatively charged cell membranes. In this study the cytotoxic effect of the antimicrobial peptide, LfcinB was tested in a panel of human neuroblastoma cell lines. LfcinB displayed a selective cytotoxic activity against both MYCN-amplified and non-MYCN-amplified cell lines. Non-transformed fibroblasts were not substantially affected by LfcinB. Treatment of neuroblastoma cells with LfcinB induced rapid destabilization of the cytoplasmic membrane and formation of membrane blebs. Depolarization of the mitochondria membranes and irreversible changes in the mitochondria morphology was also evident. Immuno- and fluorescence-labeled LfcinB revealed that the peptide co-localized with mitochondria. Furthermore, treatment of neuroblastoma cells with LfcinB induced cleavage of caspase-6, -7 and -9 followed by cell death. However, neither addition of the pan-caspase inhibitor, zVAD-fmk, or specific caspase inhibitors could reverse the cytotoxic effect induced by LfcinB. Treatment of established SH-SY-5Y neuroblastoma xenografts with repeated injections of LfcinB resulted in significant tumor growth inhibition. These results revealed a selective destabilizing effect of LfcinB on two important targets in the neuroblastoma cells, the cytoplasmic- and the mitochondria membrane.     

An ethnopharmacological survey of plants used for wound healing in Dogonland, Mali, West Africa

Traditional medicine, being a significant element in the cultural patrimony, still remains the main recourse for a large majority of people in Dogonland, Mali, for treating various diseases and ailments. This paper reports an ethnopharmacological study in Dogonland with the aim to identify medicinal plants used in the treatment of wounds. Information obtained from traditional healers revealed 73 plant species being used as wound healing remedies, according to the definitions of wounds given by the healers themselves. The plants, belonging to 34 plant families, are used as first aids, in the washing of wounds, extraction of pus, as coagulants, as well as for infected wounds. The most frequently used preparations are decoctions and powdered plant material.     

Development of a population pharmacokinetic model for carbamazepine based on sparse therapeutic monitoring data from pediatric patients with epilepsy

BACKGROUND: Population models can be important extensions of therapeutic drug monitoring (TDM), as they allow estimation of individual pharmacokinetic parameters based on a small number of measured drug concentrations. OBJECTIVE: This study used a Bayesian approach to explore the utility of routinely collected and sparse TDM data (1 sample per patient) for carbamazepine (CBZ) monotherapy in developing a population pharmacokinetic (PPK) model for CBZ in pediatric patients that would allow prediction of CBZ concentrations for both immediate- and controlled-release formulations. METHODS: Patient and TDM data were obtained from a pediatric neurology outpatient database. Data were analyzed using an iterative 2-stage Bayesian algorithm and a nonparametric adaptive grid algorithm. Models were compared by final log likelihood, mean error (ME) as a measure of bias, and root mean squared error (RMSE) as a measure of precision. RESULTS: Fifty-seven entries with data on CBZ monotherapy were identified from the database and used in the analysis (36 from males, 21 from females; mean [SD] age, 9.1 [4.4] years [range, 2-21 years]). Preliminary models estimating clearance (Cl) or the elimination rate constant (K(el)) gave good prediction of serum concentrations compared with measured serum concentrations, but estimates of Cl and K(el) were highly correlated with estimates of volume of distribution (V(d)). Different covariate models were then tested. The selected model had zero-order input and had age and body weight as covariates. Cl (L/h) was calculated as K(el) . V(d), where K(el) = [K(i) - (K(s) . age)] and V(d) = [V(i) + (V(s) . body weight)]. Median parameter estimates were V(i) (intercept) = 11.5 L (fixed); V(s) (slope) = 0.3957 L/kg (range, 0.01200-1.5730); K(i) (intercept) = 0.173 h(-1) (fixed); and K(s) (slope) = 0.004487 h(-1) . y(-1) (range, 0.0001800-0.02969). The fit was good for estimates of steady-state serum concentrations based on prior values (population median estimates) (R = 0.468; R(2) = 0.219) but was even better for predictions based on individual Bayesian posterior values (R(2) = 0.991), with little bias (ME = -0.079) and good precision (RMSE = 0.055). CONCLUSIONS: Based on the findings of this study, sparse TDM data can be used for PPK modeling of CBZ clearance in children with epilepsy, and these models can be used to predict Cl at steady state in pediatric patients. However, to estimate additional pharmacokinetic model parameters (eg, the absorption rate constant and V(d)), it would be necessary to combine sparse TDM data with additional well-timed samples. This would allow development of more informative PPK models that could be used as part of Bayesian dose-individualization strategies.     

Age at menarche in relation to maternal use of tobacco, alcohol, coffee, and tea during pregnancy

To investigate the potential effects of common early life exposures on age at menarche, the authors examined data collected in a follow-up study of pregnancies that occurred during the 1960s in California. Among 994 female offspring interviewed as adolescents, 98% had started their menstrual periods at a mean age of 12.96 years. After adjustment, the mean age at menarche was a few months earlier among girls whose mothers smoked a pack or more of cigarettes daily during pregnancy compared with unexposed girls (difference = -0.22 years, 95% confidence interval (CI): -0.49, 0.05) and more so among girls who were not White (difference = -0.52 years, 95% CI: -1.1, 0.08). Girls with both high prenatal and childhood passive smoke exposure had an adjusted mean age at menarche about 4 months earlier than those unexposed. The daughter's mean age at menarche varied little by maternal prenatal alcohol consumption. Daughters of tea consumers had a later mean age (difference = 0.41 years at >/= 3 cups (0.7 liter)/day, 95% CI: 0.03, 0.80) and were more likely to start menarche later (>13 years) (odds ratio = 1.7, 95% CI: 0.91, 3.2), but daughters of coffee consumers did not. These suggestive findings, which merit further investigation, may be related to hormonal effects.     

Reproducibility of classification in non-squamous cell carcinomas of the uterine cervix

OBJECTIVE: Reproducibility of histopathologic classification systems is of major importance for their utility in daily practice and in research. The reproducibility of histologic classification of non-squamous carcinomas (non-SCC) of the uterine cervix was evaluated, using population-based material from two 5-year periods in Norway. METHODS: Histologic slides from 388 tumors were reviewed by three experienced pathologists and analyzed for inter- and intraobserver agreement on histological subtypes and grade. RESULTS: Kappa values of inter- and intraobserver agreement were moderate to substantial for all major adenocarcinoma subgroups (endocervical, endometrioid, clear cell, or serous carcinoma), and fair to poor for mixed carcinomas and adenocarcinomas not otherwise specified (NOS). Interobserver agreement on villoglandular and adenosquamous carcinomas was poor, and the distinction of adenocarcinoma in situ from well-differentiated carcinoma proved difficult. Reproducibility of the high-risk subgroups of small cell and undifferentiated carcinomas was acceptable from a statistical point of view (kappa values >0.50). However, the authors agreed upon the diagnosis of small cell carcinomas and undifferentiated carcinomas only in 2/3 of these high-risk diagnoses. Patients with high-risk diagnoses showed significantly lower overall survival than patients with non-high-risk diagnoses (P < 0.001). This inferior survival was independent of whether the reviewers had agreed on the high-risk diagnosis or not. CONCLUSION: Clinicians should be aware of the potential inconsistencies of histopathologic diagnoses. No histopathological classification system will ever be perfectly reproducible. Future histopathologic classification of the uterine cervix should emphasize the distinction between groups of particularly low or high prognostic risks.     

Change in prevalence of IgE sensitization and mean total IgE with age and cohort

BACKGROUND: Cross-sectional studies show that the prevalence of IgE sensitization is lower in older age groups than younger age groups. This could reflect either a decrease in sensitization with aging or a higher prevalence of sensitization in more recent birth cohorts. OBJECTIVE: To assess change in IgE sensitization and mean total IgE in young adults as they age. METHODS: Serum specific IgE to common allergens and total IgE were measured on 2 occasions about 9 years apart in 6371 young adults living in 28 centers, mainly in Western Europe, who took part in the European Community Respiratory Health Survey II. Outcomes were analyzed by using generalized estimating equations, and adjustments were made for differences between laboratory measures on the 2 occasions. RESULTS: Overall, there was no net change in the prevalence of sensitization to at least 1 of house dust mite, grass, or cat (net change per 10 years of follow-up, -0.1%; 95% CI, -1.7% to 1.5%), although there was a fall in mean total IgE (ratio of geometric mean total IgE, 0.86; 95% CI, 0.79 to 0.93). There was evidence that sensitization to at least 1 allergen was higher in more recent cohorts, and this was largely explained by a higher prevalence of sensitization to grass. CONCLUSION: The disease burden associated with IgE sensitization in adults, and particularly with IgE sensitization to grass, is likely to continue to increase for some time despite current evidence that the increase in allergy seen in children may have ceased.     

Pet-keeping in childhood and adult asthma and hay fever: European community respiratory health survey

BACKGROUND: Whether pet-keeping early in life protects against or promotes allergy remains unclear. OBJECTIVE: Our aim was to examine the effects of childhood pet-keeping on adult allergic disease in a large international population-based study, including information on sensitization, adult pet-keeping, and pet prevalence in the populations. METHODS: We used information from structured interviews (n = 18,530) and specific IgE to common aeroallergens in blood samples (n = 13,932) from participants in the European Community Respiratory Health Survey (ECRHS) to analyze the associations between keeping pets and adult asthma and hay fever. RESULTS: Keeping cats in childhood was associated with asthma only among atopic subjects, an association that varied between centers (P =.002) and was stronger where cats where less common (< 40% cats: odds ratio(wheeze) [OR(wheeze)] = 1.84, 95% CI = 1.31-2.57; 40%-60% cats: OR(wheeze) = 1.33, 95% CI = 1.10-1.61; > or =60% cats: OR(wheeze) = 0.98, 95% CI = 0.73-1.33). Dogs owned in childhood or adulthood were associated with asthma among nonatopic subjects (childhood: OR(wheeze) = 1.28, 95% CI = 1.13-1.46; adulthood: OR(wheeze) = 1.31, 95% CI = 1.14-1.51; both: OR(wheeze) = 1.69, 95% CI = 1.40-2.04). In atopic subjects, those who had owned dogs in childhood had less hay fever (OR = 0.85; 95% CI = 0.73-0.98) and no increased risk of asthma (OR(wheeze) = 1.01, 95% CI = 0.87-1.17). Respiratory symptoms were more common in subjects who had owned birds during childhood (OR(wheeze) = 1.12; 95% CI = 1.02-1.23) independent of sensitization. CONCLUSIONS: The effects of pet-keeping in childhood varied according to the type of pet, the allergic sensitization of the individual, and the wider environmental exposure to allergen. Cats owned in childhood were associated with more asthma in sensitized adults who grew up in areas with a low community prevalence of cats. Dogs owned in childhood seemed to protect against adult allergic disease but promote nonallergic asthma.