Sex-matched Siblings Research Articles

Association of Vitamin D Deficiency and Vitamin D Receptor Gene Polymorphisms with Type 1 Diabetes Risk: A South Indian Familial Study

Vitamin D is a potent immune modulator and is associated with autoimmune diseases, including type 1 diabetes (T1D). The vitamin D levels and its receptor gene polymorphisms together in T1D are not yet investigated in the South Indian population. The present study focused on exploring the significance of vitamin D levels and vitamin D receptor (VDR) gene polymorphisms with the risk of developing T1D in the South Indian population. Patients with T1D and unaffected first-degree relatives (FDRs) were included in this study. Genotyping of VDR polymorphisms at four different loci (FokI- F/f, BsmI- B/b, TaqI- T/t, and ApaI- A/a) was assessed through the amplification refractive mutation system-polymerase chain reaction method. Serum vitamin D levels were measured in 98 T1D patients and 75 age- and sex-matched siblings. A total of 120 patients with T1D and 214 FDRs were included. Vitamin D deficiency (VDD) was observed in a higher proportion of T1D patients than in controls (52% vs. 32%; p<0.03). The frequency of the FokI-FF genotype was significantly higher [odds ratio (OR)=1.66; p<0.03] in T1D patients conferring a susceptible association with the disease. Nevertheless, the increased frequency of heterozygous Ff genotype (OR=0.57; p<0.02) among controls may confer a protective association with T1D. Furthermore, the transmission disequilibrium test revealed over-transmission of ApaI-A (T: U=15/5; p<0.006) and BsmI-B alleles (T: U=17/5; p<0.01) and under-transmission of BsmI-b/ApaI-a/TaqI-T haplotype (T: U=5.4/14.4; p=0.04) from parents to T1D patients. The present study concludes that VDD is the major contributing risk factor to T1D development in the South Indian population. Furthermore, the FokI-FF genotype, BsmI-B, and ApaI-A alleles were positively associated with T1D. In contrast, the FokI-Ff genotype and BsmI-b/ApaI-a/TaqI-T haplotype were negatively associated with T1D.

Parenthood for childhood cancer survivors: unfounded fear of cancer development in offspring and related health behaviors.

Current literature reveals no increased risk for adverse non-hereditary health outcomes in the offspring of childhood cancer survivors (CCS), yet survivors reported concerns regarding their offspring's health. To investigate how the fear of cancer development in offspring influences parental behavior related to health and prevention, survey reports from 256 European adult CCS and 256 age- and sex-matched siblings who participated in a multicenter study on offspring health were analyzed in the present study. Analyses of covariance and chi-square tests were conducted to test for differences between CCS and siblings in outcome variables (all related to healthy parenting behavior). CCS reported higher fear levels (p = 0.044, Partial η2 = 0.01) and less alcohol consumption (p = 0.011, Phi = 0.12) and smoking (p = 0.022, Phi = 0.11) during pregnancy than siblings. In survivor families, children were breastfed less often (p < 0.001, Phi = 0.18). Partial correlation analyses showed that CCS' fear levels decreased with increasing age (r = -0.16, p = 0.014), time since oncological therapy (r = -0.19, p = 0.003), and number of children (r = -0.21, p = 0.001). Overall, due to their own experiences with cancer, many CCS harbor misperceptions regarding the health outcomes of their offspring. Although the fear decreases with increasing distance from the active disease, any fear should be taken seriously, even if unfounded, and combated through targeted educational measures.

Identification of Baseline Characteristics That Predict Good Outcome of Allogeneic Hematopoietic Cell Transplantation in Young Chronic Lymphocytic Leukemia Patients - a Retrospective Analysis from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

Patients with relapsed/refractory chronic lymphocytic leukemia (CLL) have excellent responses with kinase or BCL2 inhibitors, but patients with high risk cytogenetics (del(17p) and/or del(11q)) do not seem to achieve long-term disease control. Allogeneic hematopoietic stem cell transplantation (alloHCT) can result in sustained progression-free survival. As non-relapse mortality (NRM) after alloHCT is partly age-dependent, alloHCT is preferably considered in younger high cytogenetic risk CLL patients, but data of early NRM and longer-term PFS lack for this age group. We focused in this study on younger allo-transplanted CLL patients (<50 years) in an EBMT registry cohort with additional data collection (n=197, median follow-up 90.4 months). The most important prognostic factor for 2-year NRM in multivariate analysis was the donor HLA match: HR 2.5, 95% CI: 1.1-5.4 for an HLA-matched unrelated donor, and HR 4.0, 95% CI: 1.4-11.6 for an HLA-mismatched unrelated donor, both versus a matched sibling (Table 1). Predictors for poor 8-year PFS were "no remission at the time of alloHCT" (HR 1.7 (95% CI: 1.1-2.5)) and partially HLA-mismatched unrelated donor (HR 2.8 (95% CI: 1.5-5.2))(Table 2). High risk cytogenetics did not have a significant impact on 8-year PFS. Based on the regression model, a reference patient was created with high risk cytogenetics (del(17p) and/or del(11q)) and "good transplant" characteristics (remission at the time of alloHCT and HLA- and sex-matched sibling donor). The predicted two-year NRM for this patient was 12.1% (95% CI: 2.5%-21.7%)(Figure A) and 8-year PFS 53.5% (95% CI: 38.0%-69.0%)(Figure B). Such a low predicted NRM may keep up with the 9% "real-world" reported 1-year NRM of ibrutinib and the 8-year PFS compares favorably to outcomes after using kinase inhibitors or venetoclax. Taking into account the amount of uncertainty for predicting survival after alloHCT but also for the sequential administration of kinase inhibitors and venetoclax, alloHCT still remains a valid option for younger high cytogenetic risk refractory/relapsed CLL patients with a 10/10 HLA-allele matched donor. [Display omitted] [Display omitted] [Display omitted] DisclosuresDreger:Novartis: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Delgado:Janssen: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Schoenland:Jansen: Honoraria, Other: financial support of conference participation, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schetelig:Sanofi: Honoraria.

Differences in neuropsychological and behavioral parameters and brain structure in patients with familial adenomatous polyposis: a sibling-paired study.

BackgroundFamilial adenomatous polyposis (FAP) is an autosomal dominant hereditary colon cancer syndrome caused by mutations in adenomatous polyposis coli (APC) with both colonic and extra-colonic manifestations. Case reports have noted an association with FAP and intellectual disability and animal studies have shown that APC is implicated in neural development and function, but no studies have investigated neuropsychological, behavioral, or structural brain characteristics of patients with FAP.MethodsWe undertook a pilot, sibling-pair study comparing three patients with FAP to their sex-matched siblings without FAP. Each sibling pair underwent neuropsychological testing by a blinded examiner, high resolution brain MRI scans, and the mother of each pair rated her children’s adaptive life skills and behavioral and emotional characteristics. Given the small number of study participants in this pilot study, quantitative comparisons of results were made by subtracting the score of the non-FAP sibling from the FAP patient on the various neuropsychological tests and parent rating questionnaires to calculate a difference, which was then divided by the standard deviation for each individual test to determine the difference, corrected for the standard deviation. Diffusion numbers in multiple regions of the brain as assessed by MRI were calculated for each study participant.ResultsWe found similarity between siblings in all three pairs on a wide range of neuropsychological measures (general intelligence, executive function, and basic academic skills) as tested by the psychologist as well as in descriptions of adaptive life skills as rated by mothers. However, mothers’ ratings of behavioral and emotional characteristics of two of the three pairs showed differences between the siblings, specifically that the patients with FAP were found to have more behavioral and emotional problems compared to their siblings. No differences in brain structure were identified by MRI.ConclusionWe report the first study exploring neuropsychological, behavioral, emotional, and structural brain characteristics of patients with FAP and found subjective differences as assessed by maternal perception in behavioral and emotional characteristics in patients with FAP compared to their siblings. Larger studies are needed to elucidate the relationship, if any, between FAP and brain function.

Risk of Advanced Adenomas in Siblings of Individuals With Advanced Adenomas: A Cross-Sectional Study

The risk of colorectal neoplasms among siblings of patients with advanced adenomas is not clear. We determined the prevalence of advanced adenomas in the siblings of patients with advanced adenomas and compared it with that of siblings of individuals without these lesions. In a blinded, cross-sectional study, colonoscopies were performed (from 2010 through 2014), at 2 hospitals in Hong Kong on 200 asymptomatic siblings of patients with advanced adenomas (exposed; mean age, 58.2 ± 6.3 years; adenomas ≥10 mm, high-grade dysplasia, villous, or tubulovillous) and 400 age- and sex-matched siblings of subjects with normal findings from colonoscopies and no family history of colorectal cancer (unexposed; mean age, 58.1 ± 6 years). We recruited 1 sibling per family. The primary outcome was prevalence of advanced adenomas. Baseline demographics (ie, aspirin use, smoking, body mass index, and metabolic diseases) did not differ significantly between exposed and unexposed individuals. The prevalence of advanced adenoma was 11.5% among the exposed subjects and 2.5% among the unexposed subjects (matched odds ratio [mOR] = 6.05; 95% confidence interval [CI]: 2.74-13.36; P < .001). The prevalence of adenomas ≥10 mm was higher among exposed than unexposed siblings (10.5% vs 1.8%; mOR = 8.59; 95% CI: 3.44-21.45; P < .001), as was the prevalence of villous adenomas (5.5% vs 1.3% in unexposed; mOR = 6.28; 95% CI: 2.02-19.53; P = .001) and all colorectal adenomas (39.0% vs 19.0% in unexposed; mOR = 3.29; 95% CI: 2.16-5.03; P < .001). Two cancers were detected in exposed siblings and none in unexposed siblings. In a cross-sectional study of subjects undergoing colonoscopy in Hong Kong, siblings of individuals with at least 1 advanced adenoma had a 6-fold increased odds of advanced adenoma compared with subjects who had a sibling with a screening colonoscopy with no identified neoplasia. ClinicalTrials.gov, Number: NCT01593098.

Shared Predisposition in the Association Between Cannabis Use and Subcortical Brain Structure.

Prior neuroimaging studies have suggested that alterations in brain structure may be a consequence of cannabis use. Siblings discordant for cannabis use offer an opportunity to use cross-sectional data to disentangle such causal hypotheses from shared effects of genetics and familial environment on brain structure and cannabis use. To determine whether cannabis use is associated with differences in brain structure in a large sample of twins/siblings and to examine sibling pairs discordant for cannabis use to separate potential causal and predispositional factors linking lifetime cannabis exposure to volumetric alterations. Cross-sectional diagnostic interview, behavioral, and neuroimaging data were collected from community sampling and established family registries from August 2012 to September 2014. This study included data from 483 participants (22-35 years old) enrolled in the ongoing Human Connectome Project, with 262 participants reporting cannabis exposure (ie, ever used cannabis in their lifetime). Cannabis exposure was measured with the Semi-Structured Assessment for the Genetics of Alcoholism. Whole-brain, hippocampus, amygdala, ventral striatum, and orbitofrontal cortex volumes were related to lifetime cannabis use (ever used, age at onset, and frequency of use) using linear regressions. Genetic (ρg) and environmental (ρe) correlations between cannabis use and brain volumes were estimated. Linear mixed models were used to examine volume differences in sex-matched concordant unexposed (n = 71 pairs), exposed (n = 81 pairs), or exposure discordant (n = 89 pairs) sibling pairs. Among 483 study participants, cannabis exposure was related to smaller left amygdala (approximately 2.3%; P = .007) and right ventral striatum (approximately 3.5%; P < .005) volumes. These volumetric differences were within the range of normal variation. The association between left amygdala volume and cannabis use was largely owing to shared genetic factors (ρg = -0.43; P = .004), while the origin of the association with right ventral striatum volumes was unclear. Importantly, brain volumes did not differ between sex-matched siblings discordant for use (fixed effect = -7.43; t = -0.93, P = .35). Both the exposed and unexposed siblings in pairs discordant for cannabis exposure showed reduced amygdala volumes relative to members of concordant unexposed pairs (fixed effect = 12.56; t = 2.97; P = .003). In this study, differences in amygdala volume in cannabis users were attributable to common predispositional factors, genetic or environmental in origin, with little support for causal influences. Causal influences, in isolation or in conjunction with predispositional factors, may exist for other brain regions (eg, ventral striatum) or at more severe levels of cannabis involvement and deserve further study.

Long-term cardiac abnormalities after cranial radiotherapy in childhood cancer survivors

Background. Cardiac morbidity is an important late effect in long-term childhood cancer survivors (CCS) treated with cardiotoxic agents or radiotherapy (RT) on the chest. However, there is limited data on the long-term cardiac sequelae in CCS who only received cranial RT. We hypothesized that cranial RT might negatively influence cardiac structure and function.Methods and results. We studied 13 CCS [mean age 30.8 (18.1–39.3) years, 7 males] who received RT only on the head for a cranial tumor and 36 age- and sex-matched healthy sibling controls. Echocardiographic follow-up was performed at median 21.7 (12.6–30.8) years after diagnosis. CCS had lower indexed diastolic LV volumes [56.0 (31.4–68.3) vs. 60.5 (41.9–94.3) mL/m2, p = 0.024]. CCS also had reduced LV systolic and diastolic function, reflected by lower systolic LV myocardial velocities (5.3 ± 0.9 vs. 7.1 ± 1.7 cm/s, p = 0.001) and longitudinal deformation (− 17.3 ± 3.1 vs. − 20.7 ± 2.0%, p < 0.001), as well as lower diastolic LV myocardial velocities (− 10.7 ± 1.7 vs. − 12.2 ± 1.5 cm/s, p = 0.006) and deformation speed (1.1 ± 0.3 vs. 1.5 ± 0.2 1/s, p = 0.005). Additionally, in CCS insulin-like growth factor levels [15.4 (9.2–34.6) vs. 24.4 (14.8–55.5) nmol/L, p = 0.007] were lower.Conclusion. Cranial RT in CCS is associated with smaller cardiac volumes and reduced systolic and diastolic LV function. This off target effect of RT might be related to lower insulin-like growth factor levels.

Spatial function in adolescents and young adults with congenital adrenal hyperplasia: Clinical phenotype and implications for the androgen hypothesis

Females with the classic form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are said to perform better than unaffected female controls on tests of mental rotation or other visuospatial abilities, but findings are conflicting. We studied 31 adolescents and young adults with CAH and 19 unaffected sibling controls, who were given standardized spatial tests and tests of other sexually differentiated cognitive functions (verbal fluency, perceptual speed). The possible role of CAH subtype (salt-wasting or simple-virilizing) was evaluated. Only females with the more severe, salt-wasting form of CAH, but not females with the simple-virilizing form, performed significantly better than sex-matched sibling controls on measures of mental rotation. Subtype differences were not significant for verbal fluency or perceptual speed. Severity of prenatal genital virilization, but not postnatal age when medication was started, predicted accuracy on the Mental Rotations Test. Results are consistent with the possibility of an organizational effect of androgens in the central nervous system that impacts the development of spatial abilities. Implications for the timing of the hypothetical critical period are discussed.

Autosomal dominant polycystic kidney disease with ectopic unilateral multicystic dysplastic kidney

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder. In most cases, ADPKD similarly affects bilateral kidneys.Case presentationAmong the 605 ADPKD patients that were followed up by our center, we identified two male patients with unilateral ADPKD. The cases were remarkable because the patients also had ectopia and multicystic dysplasia in the contralateral kidney, which are generally sporadic disease conditions. Both patients tested positive for polycystic kidney disease 1 mutation, but negative for hepatocyte nuclear factor 1 beta mutation. Moreover, the deterioration of their kidney function seemed to be quicker than their age- and sex-matched controls and siblings. Both patients had started a long-term hemodialysis in their 40s.ConclusionAnatomical and genetic abnormality in patients with ADPKD may be more frequent and complex than previously believed. The compensatory capacity in patients with ADPKD is fragile, and missing one kidney could accelerate the deterioration of renal function.

Speech tempo and fundamental frequency patterns: A case study of male monozygotic twins and an age- and sex-matched sibling

This case study describes an investigation into the speaking characteristics of a set of male monozygotic (MZ) twins (T1 and T2) and an age- and sex-matched sibling (S). Measures of speech tempo and fundamental frequency (F0) were analysed in the speech samples of a reading passage. Results showed significant between-sibling differences for sentence durations and F0 parameters; however, Euclidean distance (ED) measures revealed the smallest distances between the F0 parameters of the MZ twins. The smallest ED values were also observed between T1 and T2 for word durations, pause durations, all-voiced sample durations, and all the all-voiced sample F0 parameters. Greater similarities were observed across all three siblings for the speech tempo and dynamic F0 parameters.

Increased Risk of Advanced Neoplasms Among Asymptomatic Siblings of Patients With Colorectal Cancer

Colorectal cancer (CRC) is the second-most common cancer in Hong Kong. Relatives of patients with CRC have an increased risk of colorectal neoplasm. We assessed the prevalence of advanced neoplasms among asymptomatic siblings of patients with CRC. Patients with CRC were identified from the Prince of Wales Hospital CRC Surgery Registry from 2001 to 2011. Colonoscopies were performed for 374 siblings of patients (age, 52.6 ± 7.4 y) and 374 age- and sex-matched siblings of healthy subjects who had normal colonoscopies and did not have a family history of CRC (controls, 52.7 ± 7.4 y). We identified individuals with advanced neoplasms (defined as cancers or adenomas of at least 10 mm in diameter, high-grade dysplasia, with villous or tubulovillous characteristics). The prevalence of advanced neoplasms was 7.5% among siblings of patients and 2.9% among controls (matched odds ratio [mOR], 3.07; 95% confidence interval [CI], 1.5-6.3; P = .002). The prevalence of adenomas larger than 10 mm was higher among siblings of patients than in controls (5.9% vs 2.1%; mOR, 3.34; 95% CI, 1.45-7.66; P = .004), as was the presence of colorectal adenomas (31.0% vs 18.2%; mOR, 2.19; 95% CI, 1.52-3.17; P < .001). Six cancers were detected among siblings of patients; no cancers were detected in controls. The prevalence of advanced neoplasms among siblings of patients was higher when their index case was female (mOR, 4.95; 95% CI, 1.81-13.55) and had distally located CRC (mOR, 3.10; 95% CI, 1.34-7.14). In Hong Kong, siblings of patients with CRC have a higher prevalence of advanced neoplasms, including CRC, than siblings of healthy individuals. Screening is indicated in this high-risk population. ClinicalTrials.gov number: NCT00164944.

Burden of Morbidity in 10+ Year Survivors of Hematopoietic Cell Transplantation (HCT): A Report From the Bone Marrow Transplant Survivor Study (BMTSS)

Abstract 841▪FN2▪This icon denotes a clinically relevant abstract Background:High-intensity therapeutic exposures and prolonged immunosuppression increase the risk of long-term complications after HCT, with an attendant increase in the healthcare needs of these long-term survivors. We have previously demonstrated that morbidity increases with increasing time after HCT (Sun CL, Blood, 2010;116:3129–39). However, the burden of morbidity in patients who survive extended lengths of time after HCT and the consequent healthcare needs of these survivors are unknown. Methods:Utilizing resources offered by the BMTSS, we evaluated the risk of chronic health conditions and psychological health of 366 10+ year HCT survivors and their siblings (n=309). A severity score (grade 1 [mild]; grade 2 [moderate], grade 3[severe], grade 4 [life-threatening], and grade 5 [death due to chronic health condition]) was assigned to each health condition using the CTCAE, v3.0. Cumulative incidence of chronic health conditions was evaluated, using competing risks method. Brief Symptom Inventory (BSI) was used to describe adverse psychological health. Multivariate regression analysis allowed identification of vulnerable subgroups. The current status of healthcare utilization by the HCT survivors was also evaluated. Results:The mean age at HCT was 22 years (range: 0.4–59.8) and at study participation was 37 years (range: 11–72); mean length of follow-up was 15 years (range: 10–28). Primary diagnoses included AML (28%), ALL (17%), CML (17%), NHL (11%), aplastic anemia (11%), HL (7%), and other diagnoses (9%). Stem cell graft was autologous (27%); allogeneic related (65%) and unrelated donor (8%); 72% of the patients received TBI-based conditioning. At least one chronic health condition was reported by 74% of the HCT survivors, compared with 29% of siblings (p<0.001); 25% of the survivors reported severe/life-threatening conditions compared to only 8% of the siblings (p<0.001). Commonly reported severe/life-threatening chronic health conditions included myocardial infarction, stroke, blindness, diabetes, musculoskeletal problems, and subsequent malignancies. As shown in Figure 1A, the 15-year cumulative incidence of any chronic health condition (grades 1–5) was 71% (95% CI, 67–75%), and of severe-life-threatening conditions or death was 40% (95% CI, 33–47%). HCT survivors were 5.6 times as likely to develop a severe/life-threatening condition (95% CI, 3.7–8.6), compared with age- and sex-matched siblings. The cumulative incidence of severe/life-threatening conditions did not differ by type of HCT (p=0.79, Figure 1B). Using BSI, we evaluated somatic distress, anxiety, and depression among HCT survivors and their siblings. While the prevalence of anxiety and depression were comparable between survivors and siblings, HCT survivors were 2.7 times more likely to report somatic distress (p<0.001). Among survivors, female gender (OR=3.6, 95% CI, 1.4–9.0), low household income (<$20,000 OR=4.4, 95% CI, 1.1–17.2), and poor self-rated health status (OR=10.6, 95% CI, 4.0–27.9) were associated with increased risk for somatic distress. Fortunately, 90% of HCT survivors carried health insurance coverage, because a high proportion needed ongoing specialized medical care; 69% of the HCT survivors reported cancer/HCT-related visits at an average of 15 years after HCT. Conclusions:The burden of long-term physical and emotional morbidity borne by 10+ year HCT survivors is substantial, resulting in a high utilization of specialized healthcare. Patients, families and healthcare providers need to be made aware of the high burden, such that they can plan for post-HCT care, even many years after HCT. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Case-control study of overweight, obesity, and colorectal cancer risk, overall and by tumor microsatellite instability status.

Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%-20% of colorectal tumors display microsatellite instability (MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status. The study included 1794 case subjects with incident colorectal cancer who were identified through population-based cancer registries and 2684 of their unaffected sex-matched siblings as control subjects. Recent body mass index (BMI), BMI at age 20 years, and adult weight change were derived from self-reports of height and weight. Tumor MSI status, assessed at as many as 10 markers, was obtained for 69.7% of the case subjects and classified as microsatellite (MS)-stable (0% of markers unstable; n = 913), MSI-low (>0% but <30% of markers unstable; n = 149), or MSI-high (> or =30% of markers unstable; n = 188). Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided. Recent BMI, modeled in 5 kg/m(2) increments, was positively associated with risk of colorectal cancer for men and women combined (OR = 1.24; 95% CI = 1.15 to 1.34), for women only (OR = 1.20; 95% CI = 1.10 to 1.32), and for men only (OR = 1.30; 95% CI = 1.15 to 1.47). There was no interaction with sex (P = .22). Recent BMI, per 5 kg/m(2), was positively associated with the risk of MS-stable (OR = 1.38; 95% CI = 1.24 to 1.54) and MSI-low (OR = 1.33; 95% CI = 1.04 to 1.72) colorectal tumors, but not with the risk of MSI-high tumors (OR = 1.05; 95% CI = 0.84 to 1.31). The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status.

Systolic and diastolic dysfunction in childhood cancer survivors

10032 Background: In childhood cancer survivors (CCS), cardiac dysfunction has been mainly characterized by systolic dysfunction (SysDfx). However, both SysDfx and diastolic dysfunction (DiasDfx) are considered to be risk factors (RF) in development of clinical heart failure. Therefore, we aimed to assess the prevalence and treatment-related RF of SysDfx and DiasDfx after potential cardiovascular-toxic childhood cancer treatment (CCT). Methods: A cross-sectional single centre cardiovascular cohort study was performed in 277 CCS treated between 1976–1999 with anthracyclines (A, N=199; median (range) dose 183 (50–600) mg/m2), platinum (N=22) and/or radiotherapy (RT, N=175; chestRT, N=69; neckRT, N=67). Median age at diagnosis was 9 (0–20)-y, current age 28 (18–48)-y and follow-up (FU) 18 (5–31)-y post-treatment. Cardiac assessment included echocardiography and assessment of N-terminal pro-brain natriuretic peptide (NTproBNP). Results were compared with those of 130 age- and sex-matched sibling controls. By multivariate logistic regression, we studied the influence of CCT on the main outcome measures SysDfx (wall motion score index >1.00) and DiasDfx (E/A-ratio <1.00 and/or mean Tissue Velocity Imaging of early diastole <8.00cm/s). We adjusted for age at diagnosis, sex, current age, hypertension and BMI. Results: Clinical heart failure was found in 15 (5%) CCS. Compared with controls, CCS had a higher prevalence of SysDfx (13% vs. 2%; p<0.001) and DiasDfx (15% vs. 2%; p<0.001). In 26/40 (65%) CCS with DiasDfx no SysDfx was found. Overall, 68 (25%) CCS vs. 4 (3%) controls (p<0.001) had SysDfx and/or DiasDfx and CCS had a higher NTproBNP (47 (11–4758) vs. 34 (11–257) ng/L; p<0.001). SysDfx was associated with A-dose (by 100mg/m2; OR (95%CI) 1.4 (1.1–1.8)), not with chestRT (OR 1.1 (0.5- 2.6)). DiasDfx was associated with hypertension (OR 6.1 (2.4–15.7)), A-dose (by 100mg/m2; OR 1.4 (1.1–1.8)), chestRT (OR 3.5 (1.3–9.0)) and neckRT (OR 2.7 (1.1–7.1)). Conclusion: At median 18-y FU, 25% of CCS treated with potential cardiovascular-toxic CCT had evidence of SysDfx and/or DiasDfx. For DiasDfx, anthracycline-dose and chest-/neckRT were identified as RF. DiasDfx may be of prognostic significance in development of clinical heart failure and needs to be explored as potential intervention target. No significant financial relationships to disclose.

Parental prey selection affects risk-taking behaviour and spatial learning in avian offspring

Early nutrition shapes life history. Parents should, therefore, provide a diet that will optimize the nutrient intake of their offspring. In a number of passerines, there is an often observed, but unexplained, peak in spider provisioning during chick development. We show that the proportion of spiders in the diet of nestling blue tits, Cyanistes caeruleus, varies significantly with the age of chicks but is unrelated to the timing of breeding or spider availability. Moreover, this parental prey selection supplies nestlings with high levels of taurine particularly at younger ages. This amino acid is known to be both vital and limiting for mammalian development and consequently found in high concentrations in placenta and milk. Based on the known roles of taurine in mammalian brain development and function, we then asked whether by supplying taurine-rich spiders, avian parents influence the stress responsiveness and cognitive function of their offspring. To test this, we provided wild blue tit nestlings with either a taurine supplement or control treatment once daily from the ages of 2-14 days. Then pairs of size- and sex-matched siblings were brought into captivity for behavioural testing. We found that juveniles that had received additional taurine as neonates took significantly greater risks when investigating novel objects than controls. Taurine birds were also more successful at a spatial learning task than controls. Additionally, those individuals that succeeded at a spatial learning task had shown intermediate levels of risk taking. Non-learners were generally very risk-averse controls. Early diet therefore has downstream impacts on behavioural characteristics that could affect fitness via foraging and competitive performance. Fine-scale prey selection is a mechanism by which parents can manipulate the behavioural phenotype of offspring.

Donor KIR Genotype Does Not Affect VZV Reactivation after Allogeneic Haematopoietic Stem Cell Transplantation.

Background. Varicella zoster virus (VZV) reactivation is a common occurrence after allogeneic haematopoietic stem cell transplant (HSCT) and a cause of significant morbidity. We have recently demonstrated the protective effect of donor KIR genotpye against cytomegalovirus (CMV) reactivation- specifically the protective effect of the broad 'B' haplotype containing multiple activating KIR genes1. This retrospective study was designed to investigate whether donor KIR genotype confers an equivalent protective effect against VZV reactivation.Method. 152 patients who underwent allogeneic HSCT at a single centre were identified. Those with pre-transplant serology consistent with previous exposure to VZV were defined as at risk of VZV reactivation. All patients received aciclovir 800mg daily as routine prophylaxis. The diagnosis of VZV reactivation was made clinically. Cases of VZV reactivation were identified by examination of the case records. KIR genotyping was performed on donor DNA using PCR-SSP. The individual KIR genes KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5 and 3DS1, as well as the broad KIR haplotypes 'A' and 'B', were assessed by univariate and multivariate analysis for an effect on VZV reactivation. Also assessed was the impact of recipient HLA-C type, recipient HLA-Bw4/Bw6, donor type (sex-matched sibling, sex-mismatched sibling, volunteer unrelated), reduced intensity conditioning (RIC) regimen, the use of alemtuzemab as in vivo T cell depletion, CMV reactivation, and grade 2 or greater GVHD requiring steroid therapy.Results. 128 (84.2%) patients had evidence of past infection and thus were deemed at risk of VZV reactivation. Of these, 47 (36.7%) had clinical evidence of reactivation. 60% of transplants were from a donor possessing the broad 'B' haplotype. The rate of reactivation in the presence of donor 'B' haplotype was 40% compared to 32% when no donor 'B' haplotype was present (p=0.237). None of the individual donor KIRs were shown to significantly reduce the rate of VZV reactivation. Neither the use of a RIC regimen nor the presence of alemtuzemab in the conditioning regimen were shown to have an impact. None of the other factors analysed were associated with an increased rate of zoster reactivation.Conclusion. Donor KIR genotype does not influence VZV reactivation after allogeneic HSCT. This contrasts with the findings for CMV reactivation. No influence of donor type, conditioning or GVHD could be demonstrated. This suggests 1) that there are differing mechanisms that control the reactivation of different Herpes viruses after transplantation and 2) that KIRs may have specificity for CMV.

Genetic Disparity between Stem Cell Transplant Patients and Their Donors Assessed by High Density Single Nucleotide Polymorphism (SNP) Microarray Typing Is Seen in Specific Genomic Regions.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Advances in molecular typing of major histocompatibility complex (MHC) alleles have decreased but not eliminated the occurrence of acute GVHD. Minor histocompatibility antigen (mHA) disparities between patients and their molecularly HLA-identical donors are likely to represent the residual targets of donor immunity. The majority of mHAs are encoded by SNPs which are disparate between patient and donor. Identification of these immunogenic SNPs would provide both a clinical benefit as well as insight into the biology of GVHD. We used Affymetrix high-density arrays to assess 10,043 SNPs spanning the entire genome. We have examined genomic DNA from 36 patient/donor pairs (21 with acute GVHD grades II-IV and 15 without GVHD). All patients and donors were HLA and sex-matched siblings and all patients received T-cell depleted transplants. T cell depletion is important in this context as it removes the potential pharmacogenomic confounding factor of differential sensitivity to immunosuppressive agents. Because the donors and recipients are related, large areas of the genome are identical by descent. Similarly sized blocks of chromosome are disparately inherited. We hypothesized that genomic regions important to the immunopathogenesis of GVHD would be more likely to be disparately inherited in pairs with GVHD than in pairs without GVHD. As a control of our method we compared the area of chromosome 6 surrounding the MHC complex and demonstrated that there was minimal SNP disparity in either GVHD pairs or asymptomatic pairs. We also focused our attention on the region of chromosome 6 outside the MHC area, hypothesizing that disparities in this area would have to result from recombination events. Interestingly the only major area of disparity on Chr 6 was in the gene GMDS, which has been proposed to play a role in the extravasation of activated lymphocytes. We then examined other chromosomes for evidence of genomic regions that that were selectively disparate in GVHD pairs. We were able to identify several genomic regions that appeared to be associated with this outcome. The Lander-Green algorithm was used to estimate the allele sharing between the siblings for each SNP marker and then the disparity score was defined as the average allele sharing of the GVHD group - average allele sharing of the asymptomatic group. The five genomic regions with the highest disparity scores (ranked in order of score) and the gene closest to the region are: 11q14.3 (gene cysteine and histidine-rich domain (CHORD)-containing, zinc binding protein 1), 9p22.2 (gene SH3GL2), 5p15 (gene KIAA0947), 10p15.1 (gene aldo-keto reductase family 1, member C4), and 9p21.2 (Chr 9 ORF 72). The highly disparate regions ranged between 70 and 2200 kb in size. Interestingly the total number of disparate SNPs was not different between pairs with GVHD and pairs without GVHD, supporting the hypothesis that a limited number of SNPs are important immunologic targets. This technique of genome-wide disparity analysis is a promising addition to our ability to define important mHA.

Continuous Complete Molecular Remission after Withdrawal of Imatinib Mesylate in Relapsed CML after Allogeneic Stem Cell Transplantation.

Imatinib mesylate (Gleevec®) has changed the treatment of chronic myelogenous leukemia (CML), but allogeneic stem cell transplantation (SCT) is still considered the only curative therapy. Moreover, several reports indicate that imatinib mesylate may also induce complete remission in relapsed CML following SCT, but it is not known, whether imatinib mesylate can be stopped after achieving complete remission. We report a patient who is in a complete molecular remission 4 months after withdrawal of imatinib mesylate therapy.A 41-year old man was diagnosed with Philadelphia chromosome (Ph)-positive CML in first chronic phase without additional cytogenetic abnormalities. Hydroxyurea therapy was started and he received allogeneic SCT from an HLA-identical and sex-matched sibling donor within one year after the initial diagnosis. The conditioning regimen consisted of cyclophosphamide and total body irradiation (12Gy). A combination with cyclosporin A (CsA) and methotrexate was administered as a graft versus host disease (GvHD) prophylaxis. Nevertheless chronic extensive GvHD of the oral mucosa developed 3 months after SCT and resolved without further therapy. CsA was tapered after 3 and stopped after 6 months. The patient achieved complete cytogenetic remission (CCR) 9 months following SCT, but BCR-ABL remained positive by reverse transcriptase polymerase chain reaction (RT-PCR). Four years after SCT he experienced cytogenetic and morphologic relapse. Donor lymphocyte infusions were not administered, because the donor was not available, and Interferon therapy was started with an escalated dose of 9 Mio units per day.With this treatment, a second CCR and also an acceptable molecular control (BCR-ABL measurements with RT-PCR between 0.3–2.5%) was achieved. The therapy was changed to imatinib mesylate (300–400mg per day) 6 years after SCT, because of persistent molecular detection of BCR-ABL. With this treatment, complete hematologic and molecular remission were attained 5 months later and 18 months after the beginning of imatinib mesylate treatment bone marrow examination revealed no abnormalities by morphological, cytogenetic or molecular analysis. Imatinib mesylate was stopped thereafter and RT-PCR to detected residual BCR-ABL transcripts was performed monthly. Four months after stopping imatinib mesylate, the patient remains in a complete molecular remission without clinical signs of GvHD.Imatinib mesylate can induce sustained complete hematologic and molecular remission in patients with relapsed CML after allogeneic SCT. The combination of the imatinib mesylate and tumor reduction by graft versus leukemia may have synergistic effects in-vivo, and therefore facilitate the withdrawal of imatinib mesylate. Thus, the presented case shows the successful withdrawal of imatinib mesylate in a patient with relapse CML 6 years after allogeneic SCT. He continues to be in a complete molecular remission 4 months after withdrawal. However controlled studies are needed to establish the role of imatinib mesylate in the posttransplant setting.

Speech Characteristics of Monozygotic Twins and a Same-Sex Sibling: An Acoustic Case Study of Coarticulation Patterns in Read Speech

This case study reports on an acoustic investigation of the motor speech characteristics of a set of young adult male monozygotic (MZ) twins and compares them to those of an age- and sex-matched sibling who participated in the study 2 years later to match for demographic factors. Coarticulation patterns were investigated from read samples of consonant-vowel sequences in monosyllabic words containing a variety of consonants and vowels. This was done by examining F₂ vowel onsets and F₂ vowel targets, plotted as F₂ locus equations. Data were processed for between-sibling differences using a number of statistical tests. Results indicated that the MZ twins displayed F₂ parameters and coarticulation patterns which were more similar than those of their age- and sex-matched sibling. The results of this case study therefore suggest that acoustic phonetic parameters used to index coarticulation patterns have the potential to profile some of the similarities and differences in the speech characteristics of genetically related individuals.

Seizures in rural Zambia.

To describe the period prevalence of epilepsy and febrile seizures in a bush hospital and discuss the medical sequelae and social impact of seizures in this population. For 13 weeks, an evaluation of inpatients was made at Chikankata Hospital in rural Zambia. Inpatients identified as having seizures, "fits," "spells," or "fainting," were evaluated by a medical records review, basic demographic data, a neurological history and physical examination, and a treatment history. A semistructured questionnaire was administered to evaluate the social impact of seizures and assess factors associated with delayed care seeking. Seizures composed 44% of all inpatient neurologic disease and resulted in 84 admissions. Epilepsy patients received treatment primarily from traditional healers; only 31% reported ever receiving antiepileptic drugs (AEDs). Among those who had received treatment, AEDs were frequently underdosed. Patients with epilepsy had significantly less education than their sex-matched siblings. Patients with untreated epilepsy for >2 years were more likely to have experienced serious burns or falls requiring hospitalization. Children with febrile seizures whose parents held supernatural beliefs regarding seizures were more likely to be treated with traditional medicines, had higher malarial parasite counts, and required longer hospitalizations than children with febrile seizures whose parents recognized the association between seizures and hyperthermia. Epilepsy and febrile seizures are responsible for a significant burden of disease in rural Zambia. Serious medical complications often result from seizures, especially if untreated for >2 years. Social stigma decreases educational opportunities and misperceptions regarding seizures may result in delayed care for children with febrile seizures. Some evidence suggests that epilepsy is underreported, underrecognized, and undertreated in this population.