Higher Cumulative Risk Research Articles

Risks of different skin tumour combinations after a first melanoma, squamous cell carcinoma and basal cell carcinoma in Dutch population-based cohorts: 1989-2009.

Skin cancer patients are primarily at increased risk of developing subsequent skin cancers of the same type. Shared risk factors might also increase the occurrence of a different type of subsequent skin cancer. To investigate risks of different skin tumour combinations after a first melanoma, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). All melanoma and SCC patients included in the national Netherlands Cancer Registry (NCR) and all BCC patients included in the regional Eindhoven Cancer Registry (ECR) between 1989 and 2009 were followed until diagnosis of a subsequent different skin cancer (melanoma, SCC or BCC), date of death or end of study. Cumulative risks, standardized incidence ratios (SIR) and absolute excess risks (AER) of subsequent skin cancers were calculated. A total of 50 510 melanoma patients and 64 054 patients with a SCC of the skin were included (national data NCR). The regional data of the ECR consisted of 5776 melanoma patients, 5749 SCC patients and 41 485 BCC patients. The 21-year cumulative risk for a subsequent melanoma after a first SCC or BCC was respectively 1.7% and 1.3% for males and 1.3% and 1.2% for females; SCC after melanoma or BCC was 4.6% and 9.3% (males) and 2.6% and 4.1% (females); BCC after melanoma or SCC was respectively 13.2% and 27.8% (males) and 14.9% and 21.1% (females). SIRs and AERs remained elevated up to 21 years after the first melanoma, SCC or BCC. This large population-based study investigating risks of developing a different subsequent cutaneous malignancy showed high-cumulative risks of mainly KC and markedly increased relative and absolute risks of all tumour combinations. These estimates confirm a common carcinogenesis and can serve as a base for follow-up guidelines and patient education aiming for an early detection of the subsequent cancers.

Association of hepatitis status with surgical outcomes in patients with dual hepatitis B and C related hepatocellular carcinoma

BackgroundThe conception that serological hepatitis markers determined surgical prognosis of hepatocellular carcinoma (HCC) associated with hepatitis B (HBV) or hepatitis C (HCV) has been well defined. However, little is known about the relationship between surgical outcomes and serological hepatitis markers in patients with dual HBV and HCV related HCC.MethodsA retrospective analysis of the clinical data of 39 HCC patients with HBV-HCV coinfection who underwent curative hepatectomy between 2001 and 2011 was performed. HBV DNA quantification, expression of HBV antigens, anti-HCV signal-to-cutoff ratio (S/CO) and some clinicopathological characteristics were investigated to show the potential relationship among them and the surgical prognosis.ResultsThe Cox proportional hazards model identified that HBV DNA quantification of 1,000 IU/mL or higher, HBeAg seropositivity, tumor size of greater than 5 cm, multiple tumors, and vascular invasion were risk factors for HCC prognosis. Thus, HBV DNA quantification, HBsAg level, HBeAg status and HCV-Ab level which may reveal the hepatitis status were further analyzed. The overall survival time in the group with high (≥1,000 IU/mL) HBV DNA quantification was significantly lower than the group with low (<1,000 IU/mL) HBV DNA quantification. Similarly, the high HBsAg level (≥1,000 IU/mL) was associated with poor survival compared with the low HBsAg level. Moreover, HBeAg seropositivity determined a higher cumulative risk for death. However, no significant difference was observed in overall survival time between the groups with low (<10.9 S/CO) and high (≥10.9 S/CO) HCV-Ab level. Compared to HCV-Ab high-level group, the serological HBsAg level was observed significantly higher in HCV-Ab low-level group. Furthermore, the data we analyzed showed these 4 serological hepatitis markers were not correlated with cumulative recurrence rate. On multivariate analysis, none of serological hepatitis markers was an independent prognostic factor for HCC patients with dual hepatitis B and C.ConclusionAmong HCC patients with HBV-HCV coinfection, those who with preoperatively high HBV DNA quantification or HBeAg seropositivity had a short survival time and served as poor survival indicators. Serological expression of HBV status rather than HCV status might potentially dominate the surgical outcomes of the Chinese HCC patients with HBV-HCV coinfection.

In risky environments, emotional children have more behavioral problems but lower allostatic load.

Developmental models of temperament by environment interactions predict that children's negative emotionality exacerbates the detrimental effects of risky environments, increasing the risk for pathology. However, negative emotions may have an adaptive function. Accordingly, the present study explores an alternative hypothesis that in the context of high adversity, negative emotionality may be a manifestation of an adaptive coping style and thus be protective against the harmful effects of a stressful environment. Prospective combined effects of negative emotionality and cumulative risk (confluence of multiple risk factors related to poverty) on children's internalizing and externalizing symptoms and allostatic load, an index of cumulative physiological dysregulation, were assessed in 239 children (46% female, baseline age = 9). Negative emotionality and cumulative risk were assessed at baseline. Internalizing and externalizing behaviors were measured at 4- and 8-year follow-ups. Allostatic load was measured at baseline and both follow-ups using neuroendocrine, cardiovascular, and metabolic parameters. Linear mixed-effect models were used to analyze the prospective associations between negative emotionality, cumulative risk, and the outcomes-allostatic load and internalizing and externalizing behaviors. The combination of high cumulative risk exposure and high negative emotionality was associated with highest levels of internalizing and externalizing behaviors. However, consistent with the alternative hypothesis, negative emotionality reduced the effects of high cumulative risk on allostatic load. In the context of risky environments, negative emotionality may offer some physical health benefits. (PsycINFO Database Record

6:2 Chlorinated polyfluorinated ether sulfonate, a PFOS alternative, induces embryotoxicity and disrupts cardiac development in zebrafish embryos

As an alternative to perfluorooctanesulfonate (PFOS), 6:2 chlorinated polyfluorinated ether sulfonate (commercial name: F-53B) has been used as a mist suppressant in Chinese electroplating industries for over 30 years. It has been found in the environment and fish, and one acute assay indicated F–53B was moderately toxic. However, the toxicological information on this compound was incomplete and insufficient for assessment of their environment impact. The object of this study was to examine the developmental toxicity of F–53B using zebrafish embryos. Zebrafish embryos were incubated in 6-well plates with various concentrations of F–53B (1.5, 3, 6, and 12mg/L) from 6 to 132h post fertilization (hpf). Results showed that F–53B exposure induced developmental toxicity, including delayed hatching, increased occurrence of malformations, and reduced survival. Malformations, including pericardial and yolk sac edemas, abnormal spines, bent tails, and uninflated swim bladders, appeared at 84 hpf, and increased with time course and dose. A decrease in survival percentages was noted in the 6 and 12mg/L F-53B-treated groups at 132 hpf. Continuous exposure to 3mg/L F–53B resulted in high accumulation levels in zebrafish embryos, suggesting an inability for embryos to eliminate this compound and a high cumulative risk to fish. We also examined the cardiac function of embryos at specific developmental stages following exposure to different concentrations, and found that F–53B induced cardiac toxicity and reduced heart rate. Even under low F–53B concentration, o-dianisidine staining results showed significant decrease of relative erythrocyte number at 72 hpf before the appearance of observed effects of F–53B on the heart. To elucidate the underlying molecular changes, genes involved in normal cardiac development were analyzed using real-time qPCR in the whole-body of zebrafish embryos. F–53B inhibited the mRNA expression of β-catenin (ctnnb2) and wnt3a. The mRNA levels of β-catenin targeted genes (nkx2.5 and sox9b), which play critical roles in cardiogenesis, were also reduced after exposure. Thus, exposure to F–53B impaired the development of zebrafish embryos and disrupted cardiac development, which might be mediated by effects on the Wnt signaling pathway and decrease of erythrocyte numbers.

Substance-abusing parents and their children in termination of parental rights cases in Israel

Parental substance abuse significantly increases the risk of child maltreatment and loss of custody. If parental capacity due to substance abuse cannot be rehabilitated within a limited time period and if the child cannot be safely returned to his/her home, the state, in various jurisdictions, is empowered to initiate termination of parental rights proceedings. Despite the connection between substance abuse and termination of parental rights, the research literature in this area is limited. Based on a sample of 212 rulings in favor of termination of parental rights by Israeli courts, the present study examines factors that differentiate substance-abusing from non-substance-abusing parents. The findings indicate that substance-abusing parents constitute a unique high-risk group among parents whose parental rights were terminated. This group is characterized by a higher cumulative risk that includes mental health issues with an emphasis on personality disorders and emotional problems, criminal records, child neglect and maternal single parenthood. All these factors, as well as the overall number of risk factors in a particular case, were found to predict substance-abusing parenthood. A discussion of the findings and their implications for social work practice with families involved in the child welfare system follows.

Li-Fraumeni Syndrome.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by a germline mutation of the TP53 gene on chromosome 17p13.1. It has an autosomal dominant pattern of inheritance with high penetrance. These patients have a very high lifetime cumulative risk of developing multiple malignancies and have a strong family history of early-onset malignancies. The protein p53, encoded by TP53, has a complex set of genome-preserving functions initiated during episodes of cellular stress and DNA damage. In LFS, TP53 gene mutations cause the loss of function of p53, leading to downstream events permissive for development of various malignancies throughout life. The LFS component tumors include soft tissue sarcomas, osteosarcoma, premenopausal breast cancer, brain tumors, and adrenal cortical carcinomas. Multiple types of sarcomas have been reported in association with LFS; this review article will focus on the most frequently encountered pediatric sarcomas associated with TP53 mutations.

Examining protective factors against violence among high-risk youth: Findings from the Seattle Social Development Project

PurposeThis paper examined proximal and distal effects of protective factors specified in the social development model (SDM) on youth violence among high-risk youth. MethodsData come from the Seattle Social Development Project, a longitudinal study of development from childhood into adulthood. A community sample of 808 participants from the Seattle Public School District was surveyed from the 5th grade through adulthood. This paper uses data from participants' adolescent years, ages 10–18. ResultsHigher levels of protective factors in early and middle adolescence reduced the odds of violence during late adolescence in the full sample and in two different risk groups (high cumulative risk and low SES). Although risk exposure increased the odds of violence, protective factors in middle adolescence predicted lower odds of violence during late adolescence. Importantly, protective factors had a greater effect in reducing violence among youth exposed to high levels of cumulative risk than among youth exposed to lower levels of cumulative risk. This difference was not observed between youth from higher and lower SES families. ConclusionProtective factors specified in the SDM appear to reduce violence in late adolescence even among youth from low SES families and youth exposed to high levels of cumulative risk.

Using big data from health records from four countries to evaluate chronic disease outcomes: a study in 114 364 survivors of myocardial infarction.

AimsTo assess the international validity of using hospital record data to compare long-term outcomes in heart attack survivors.Methods and resultsWe used samples of national, ongoing, unselected record sources to assess three outcomes: cause death; a composite of myocardial infarction (MI), stroke, and all-cause death; and hospitalized bleeding. Patients aged 65 years and older entered the study 1 year following the most recent discharge for acute MI in 2002–11 [n = 54 841 (Sweden), 53 909 (USA), 4653 (England), and 961 (France)]. Across each of the four countries, we found consistent associations with 12 baseline prognostic factors and each of the three outcomes. In each country, we observed high 3-year crude cumulative risks of all-cause death (from 19.6% [England] to 30.2% [USA]); the composite of MI, stroke, or death [from 26.0% (France) to 36.2% (USA)]; and hospitalized bleeding [from 3.1% (France) to 5.3% (USA)]. After adjustments for baseline risk factors, risks were similar across all countries [relative risks (RRs) compared with Sweden not statistically significant], but higher in the USA for all-cause death [RR USA vs. Sweden, 1.14 (95% confidence interval 1.04–1.26)] and hospitalized bleeding [RR USA vs. Sweden, 1.54 (1.21–1.96)].ConclusionThe validity of using hospital record data is supported by the consistency of estimates across four countries of a high adjusted risk of death, further MI, and stroke in the chronic phase after MI. The possibility that adjusted risks of mortality and bleeding are higher in the USA warrants further study.

Take your mind off it: Coping style, serotonin transporter linked polymorphic region genotype (5-HTTLPR), and children's internalizing and externalizing problems.

Individuals with the short variant of the serotonin transporter linked polymorphic region gene are more susceptible than individuals homozygous for the long allele to the effects of stressful life events on risk for internalizing and externalizing problems. We tested whether individual differences in coping style explained this increased risk for problem behavior among youth who were at both genetic and environmental risk. Participants included 279 children, ages 8-11, from the Children's Experiences and Development Study. Caregivers and teachers reported on children's internalizing and externalizing symptoms, and caregivers and children on children's exposure to harsh parenting and parental warmth in middle childhood, and traumatic events. Children reported how frequently they used various coping strategies. Results revealed that short/short homozygotes had higher levels of internalizing problems compared with long allele carriers and that short allele carriers had higher levels of externalizing problems compared with long/long homozygotes under conditions of high cumulative risk. Moreover, among children who were homozygous for the short allele, those who had more cumulative risk indicators less frequently used distraction coping strategies, which partly explained why they had higher levels of internalizing problems. Coping strategies did not significantly mediate Gene × Environment effects on externalizing symptoms.

Abstract 2749: Cumulative cancer risk in the NCI Li-Fraumeni Syndrome Cohort

Abstract Background: Li-Fraumeni Syndrome (LFS) is a rare hereditary cancer predisposition syndrome characterized by the early onset of a wide range of cancers and a very high lifetime cumulative cancer risk. Despite significant progress in understanding LFS, uncertainty remains regarding the cancer incidence rates and cancer spectrum for TP53 mutation carriers. In addition, the cancer incidence for members of families meeting the clinical diagnostic criteria of LFS or Li-Fraumeni like (LFL) syndrome but in which no TP53 mutation has been identified (TP53- families) has not been established. Methods: The NCI's LFS Study (NCT01443468) is a natural history study that opened to accrual in August 2011. Inclusion criteria include LFS or LFL syndrome; a germline TP53 mutation; or a personal history of choroid plexus carcinoma, adrenocortical carcinoma (ACC), or ≥3 primary cancers. Participants complete a detailed family history and individual information questionnaires. Confirmation of all reported cancer diagnoses is pursued. Results: Of the 122 families enrolled to date, 95 families have a germline TP53 mutation (TP53+ families) and 27 are TP53-families. TP53+ families: 243 mutation carriers from 95 mutation-positive families were included in the cancer risk estimates. The cumulative risk to first cancer diagnosis for the entire group is 43% by age 30 and close to 100 by age 70, with males having higher risk in childhood adolescence and females having higher risk starting in the 20s, mostly due to breast cancer. When examined by cancer type, the cumulative risk to age 70 is 35% for breast cancer, 16% for soft tissue sarcoma, 10% for brain cancer, 7% for bone cancer, 2% for leukemia, 2% for ACC, and 26% for others. Overall survival is approximately 80% by age 50. TP53- families: The underlying etiology contributing to cancer risk in the TP53- families is not known at this time; therefore, for the estimation of cancer risk among these families, we included all bloodline members belonging to the lineage contributing to the eligibility criteria. Among the 522 individuals from the 27 TP53- families, the cumulative risk to first cancer diagnosis is 7% by age 30 and 45% by age 70. The lifetime cumulative risk is higher for breast, brain, lung cancer, and melanoma compared with other cancer types. Overall survival is approximately 90% by age 50. Conclusion: We report the cumulative cancer incidence and overall survival among TP53 mutation carriers in TP53+ families as well as among members of TP53- families. Identification of additional causative gene(s) in TP53- families will help refine the cancer risk of family members. We are evaluating the risks of second primary cancers, and whether the rate is dependent on the type of the first cancer in all families. Citation Format: Phuong L. Mai, Philip S. Rosenberg, June A. Peter, Rosamma DeCastro, Payal P. Khincha, Jennifer T. Loud, Renee Bremer, Sharon A. Savage. Cumulative cancer risk in the NCI Li-Fraumeni Syndrome Cohort. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2749. doi:10.1158/1538-7445.AM2015-2749

Abstract 2740: Familial Hodgkin lymphoma by relationship, sex, age and histology: a joint study from five Nordic countries

Abstract Background: We aimed to estimate lifetime (0-79 years) cumulative risk (CR) of Hodgkin lymphoma (HL) in relatives of patients with HL by relationship, sex, age and histology. Design: A population-based cohort of 57,475 first-degree relatives of 13,922 HL patients diagnosed in 1955-2009 in Nordic countries was followed for cancer incidence. Standardized incidence ratios (SIRs) were calculated using histology-, age-, sex-, period-, and country-specific incidence rates as the reference. Results: The overall CR of HL in first-degree relatives of a patient with Hodgkin lymphoma was 0.6%, which represents 3-fold (SIR = 3.3, 95%CI = 2.8-3.9) increase over the general population risk (men 0.3%; women 0.2%). Significantly high CR (1%) was found among sisters with early-onset HL and unlike-sex siblings with HL diagnosed at age 30-59. The familial risk in sisters (9-fold) was higher than in brothers (4.5-fold) or unlike-sex siblings (6-fold). In general, the risk in siblings (6-fold) was higher than in parents/children (2-fold). Very high risk of HL was found for few men with two HL first-degree relatives (3-8%) and for twin brothers (18%). For the first time we found high familial risk of concordant histological subtypes of HL [lymphocyte-rich (81-fold, n = 6) and nodular sclerosis (4.6-fold, n = 22)] and also discordant subtypes. Conclusions: Lymphocytic-rich histology type of HL showed highest familial risk. The absolute risk of familial HL was generally less than 1.5%, except for men with multiple affected first-degree relatives (3-8%), twin brothers (18%), or brothers with early-onset HL (2%). Citation Format: Mahdi Fallah, Elham Kharazmi, Eero Pukkala, Jørgen H. Olsen, Laufey Tryggvadottir, Kristina Sundquist, Steinar Tretli, Kari Hemminki. Familial Hodgkin lymphoma by relationship, sex, age and histology: a joint study from five Nordic countries. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2740. doi:10.1158/1538-7445.AM2015-2740

Colonoscopy findings in high-risk individuals compared to an average-risk control population

Background and aims: There is clear evidence of reduced morbidity and mortality from regular colonoscopy programs in patients with Lynch syndrome (LS). Today, also individuals with empirically increased risks of colorectal cancer (CRC) are offered colonoscopic surveillance. The aim was to compare the findings at the first screening colonoscopy in LS carriers, and individuals with an increased risk of bowel cancer due to family history of CRC with a control population. Methods: Altogether 1397 individuals with an increased risk for CRC were divided in four risk groups: one with LS carriers and three groups with individuals with different family history of CRC. The findings were compared between the different risk groups and a control group consisting of 745 individuals from a control population who took part in a population-based colonoscopy study. Results: In LS, 30% of the individuals had adenomas and 10% advanced adenomas. The corresponding figures in the other risk groups were 14–24% and 4–7%, compared with 10% and 3% in the control group. The relative risk of having adenomas and advanced adenomas was, compared to controls, significantly higher for all risk groups except the group with the lowest risk. Age was a strong predictor for adenomas and advanced adenomas in both risk individuals and controls. Conclusions: Individuals with a family history of CRC have a high prevalence and cumulative risk of adenomas and advanced adenomas, and screening is motivated also in this risk group.

Chronic and acute anemia and extracranial internal carotid stenosis are risk factors for silent cerebral infarcts in sickle cell anemia

AbstractEarly transcranial Doppler (TCD) screening of the Créteil sickle cell anemia (SCA)-newborn cohort, and rapid initiation of transfusion programs, resulted in successful prevention of overt strokes, but a high cumulative risk of silent cerebral infarcts (SCI) remained, suggesting that TCD screening does not identify all patients with SCA at risk for SCI. We hypothesized that episodes of hypoperfusion/hypoxia, as observed during acute chest syndromes or acute anemic events (AAE), and extracranial internal carotid artery (eICA) stenoses, detectable via submandibular Doppler sonography and cervical magnetic resonance angiography (MRA), could also be risk factors for SCI. This study includes 189 stroke-free patients with SCA from the Créteil newborn cohort (1992-2010) followed longitudinally by magnetic resonance imaging/MRA, including cervical MRA at the last assessment. All patients with abnormal TCD and/or intracranial stenoses were placed on a transfusion program. Mean follow-up was 9.9 years (range, 2.2-19.9 years; 1844 patient-years). Annual rates of clinical events were calculated. The cumulative risk for SCI was 39.1% (95% confidence interval [CI], 23.5%-54.7%) by age 18 years, with no plateau. We confirm that baseline hemoglobin level lower than 7 g/dL before age 3 years is a highly significant predictive risk factor for SCI (hazard ratio, 2.97; 95% CI, 1.43-6.17; P = .004). Furthermore, we show that AAE rate (odds ratio, 2.64 per unit increase; 95% CI, 1.09-6.38; P = .031) and isolated eICA stenosis (odds ratio, 3.19; 95% CI, 1.18-8.70; P = .023) are significant and independent risk factors for SCI.

The Impact of Concurrent MYC BCL2 Protein Expression on the Risk of Secondary Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma (DLBCL)

Introduction: Recent studies have established that concurrent MYC and BCL2 protein expression by immunohistochemistry (IHC) identifies a subgroup of patients with diffuse large B-cell lymphoma (DLBCL) with a poor outcome. Classic dual translocation MYC/ BCL2, so called 'double hit’ disease, is associated with a high risk of central nervous system (CNS) relapse; however the impact of concurrent MYC and BCL2 protein expression on the risk of CNS relapse remains unknown. Further, robust biological markers that accurately predict the risk of CNS relapse in DLBCL would also be of value in clinical practice.Methods: Cases of pre-treatment formalin fixed paraffin embedded DLBCL in two tissue microarrays were independently scored by two expert hematopathologist (GWS and KLT or PF and AM) for expression of MYC (Epitomics Y69), BCL2 (Dako 124), CD10, BCL6 and MUM1 by IHC. MYC and BCL2 positivity were defined as ≥ 40% and ≥ 50% cells with staining, respectively, in accordance with previously established cutoffs (Johnson, JCO 2012; 30). Cases with discordant scores were reviewed by a third hematopathologist (RDG) to reach a consensus. Cell of origin (COO) was assigned according to the Hans IHC algorithm (Hans, Blood 103: 2004) as well as by the recently described gene expression profiling Lymph2Cx 20 gene assay based on NanoString technology (Scott, Blood 2014; 123) in the subset of patients with ≥ 40% tumor content. Patients treated with at least one cycle of R-CHOP chemotherapy with curative intent were included and those with established CNS disease at diagnosis were excluded.Results: 447 patients were identified with the following baseline clinical characteristics: Median age 65 y (16-92y); males n=280, 63%; performance status ≥ 2, n= 147, 33%; stage 3 or 4 disease n=242, 54%; elevated LDH n=219, 47%; EN > 1 n= 80, 17%. With a median follow-up of 6.75 years for living patients, the 3 year time to progression, progression-free and overall survival for all patients were 68%, 66%, and 73%, respectively. In total, 131 (29%) were MYC+BCL2+ and 316 (71%) were non-MYC+BCL2+. By COO assignment using the Hans algorithm (n=444), 192 were non-GCB (43%) and 252 were GCB (57%) and by the Lymph2Cx (n=308); 103 were ABC (33%), 172 were GCB (56%) and 33 (11%) were unclassifiable. The 2 year cumulative risk of CNS relapse for the whole cohort was 4.3%. The cumulative risk of CNS relapse was higher in cases that were MYC+BCL2+ (2 year risk 9.4% vs 2.4%, P=0.001) with similar results obtained if classic MYC+BCL2+ double hit cases are excluded. There were no cases of CNS relapse in cases MYC+ alone by IHC. By COO, patients with a non-GCB phenotype by the Hans algorithm had an increased risk of CNS relapse (2 year risk 6.9% vs 2.6%, P=0.03) and similarly, cases assigned as ABC DLBCL by the Lymph2Cx assay also identified a group with a higher risk of CNS relapse compared to GCB cases (9.5% vs 2.5%, P=0.03) (Figure 1). In Cox regression multivariate analysis including the COO (Hans), IPI group (0/1 vs 2/3 vs 4/5) and MYC/BCL2 IHC, only the IPI (HR 2.18, P=0.02) and MYC+BCL2+ IHC (HR=3.76, P=0.007) were associated with an increased risk of CNS relapse. Similar results were obtained using the Lymph2Cx COO designation. Within the IPI risk groups, MYC+BCL2+ status further stratified patients in the intermediate risk group (IPI 2 or 3, n=206) into a higher risk group (2 year CNS relapse 12.6%) and a low risk group (2 year CNS relapse 2.9%) (P=0.01). A similar trend was observed in the high IPI risk group (IPI 4 or 5, n=86, 2 year CNS relapse MYC+BCL2+ 17.2% vs 4.7%, P=.0.18) but it was not useful in the low IPI risk group (IP1 0 or 1 (n=155), 2 year CNS relapse 4% vs 1%, P=0.39) where the overall risk was low. Within the COO subgroups, MYC+BCL2+ status also defined a group at high cumulative risk of CNS relapse within the non-GCB subtype (12.9% vs 3%, P=0.001) and by the Lymph2Cx defined ABC subtype (16.9% vs 2.2%, P= 0.03) and a trend was observed for GCB defined by Lymph2Cx (6.6% vs 1.5%. P=.08) but not by Hans criteria (P=0.40).Conclusion: Concurrent expression of MYC and BCL2 protein in DLBCL defines a group of patients at high risk of CNS relapse, independent of the IPI and COO. MYC+BCL2+ status may help to further risk stratify patients in the intermediate and high IPI risk groups and within the ABC subtype to identify patients who should undergo additional diagnostic testing and in whom to explore the effectiveness of prophylactic CNS strategies. [Display omitted] DisclosuresSavage:F Hoffmann-La Roche: Other. Sehn:Roche: Research Funding. Connors:Seattle Genetics, Inc.: Research Funding; Roche: Research Funding. Gascoyne:Hoffman La-Roche: Research Funding.

Spatiotemporal distribution of carbonyl compounds in China

A sampling campaign was carried out at nine Chinese cities in 2010/2011. Fifteen monocarbonyls (C# = 1–9) were quantified. Temperature is the rate-determining factor of the summertime carbonyl levels. The carbonyl emissions in winter are mainly driven by the primary anthropogenic sources like automobile. A molar ratio of propionaldehyde to nonaldehyde is a barometer of the impact of atmospheric vegetation emission which suggesting that strong vegetation emissions exist in summer and high propionaldehyde abundance is caused by fossil fuel combustion in winter. Potential health risk assessment of formaldehyde and acetaldehyde was conducted and the highest cumulative risks were observed at Chengdu in summer and Wuhan in winter. Because of the strong photochemical reaction and large amount of anthropogenic emissions, high concentrations of carbonyl compounds were observed in Chengdu. The use of ethanol-blended gasoline in Wuhan is the key reason of acetaldehyde emission and action should be taken to avoid potential health risks.

Cigarette smoking prior to first cancer and risk of second smoking-associated cancers among survivors of bladder, kidney, head and neck, and stage I lung cancers.

Data on smoking and second cancer risk among cancer survivors are limited. We assessed associations between smoking before first cancer diagnosis and risk of second primary smoking-associated cancers among survivors of lung (stage I), bladder, kidney, and head/neck cancers. Data were pooled from 2,552 patients with stage I lung cancer, 6,386 with bladder cancer, 3,179 with kidney cancer, and 2,967 with head/neck cancer from five cohort studies. We assessed the association between prediagnostic smoking and second smoking-associated cancer risk with proportional hazards regression, and compared these estimates to those for first smoking-associated cancers in all cohort participants. Compared with never smoking, current smoking of ≥ 20 cigarettes per day was associated with increased second smoking-associated cancer risk among survivors of stage I lung (hazard ratio [HR] = 3.26; 95% CI, 0.92 to 11.6), bladder (HR = 3.67; 95% CI, 2.25 to 5.99), head/neck (HR = 4.45; 95% CI, 2.56 to 7.73), and kidney cancers (HR = 5.33; 95% CI, 2.55 to 11.1). These estimates were similar to those for first smoking-associated cancer among all cohort participants (HR = 5.41; 95% CI, 5.23 to 5.61). The 5-year cumulative incidence of second smoking-associated cancers ranged from 3% to 8% in this group of cancer survivors. Understanding risk factors for second cancers among cancer survivors is crucial. Our data indicate that cigarette smoking before first cancer diagnosis increases second cancer risk among cancer survivors, and elevated cancer risk in these survivors is likely due to increased smoking prevalence. The high 5-year cumulative risks of smoking-associated cancers among current smoking survivors of stage I lung, bladder, kidney, and head/neck cancers highlight the importance of smoking cessation in patients with cancer.

Adding insult to injury: Childhood and adolescent risk factors for psychosis predict lower fractional anisotropy in the superior longitudinal fasciculus in healthy adults

Although epidemiological studies provide strong support for demographic and environmental risk factors in psychotic disorders, few data examine how these risk factors relate to the putative aberrant neurodevelopment associated with illness. The present study examined how the accumulation of risk factors including low IQ, low parental socioeconomic status (SES), history of adolescent cannabis use and childhood trauma, and high levels of subclinical psychotic-like experiences (PLEs) contributed to aberrant neurodevelopmental outcomes in 112 otherwise healthy adults recruited from the community. Participants were studied with diffusion tensor imaging (DTI), and voxel-wise statistical analysis of fractional anisotropy (FA) using tract-based spatial statistics (TBSS) was used to examine the relation between cumulative risk (CR) for psychosis and white matter (WM) integrity across the whole brain. Analyses revealed that higher CR was significantly associated with lower FA in a cluster in the left superior longitudinal fasciculus (SLF). These results suggest that risk factors previously associated with psychotic disorders are associated with WM integrity even in otherwise healthy adults and may provide insight into how previously identified risk factors contribute to the structural brain abnormalities associated with psychotic illness. Prospective longitudinal studies examining the effect of risk factors on the developmental trajectory of brain WM are warranted.

The clinical utility of genetic testing in breast cancer kindreds: a prospective study in families without a demonstrable BRCA mutation

We report prospectively observed risk for breast cancer in breast cancer kindreds without a demonstrable BRCA1/2 mutation. According to family history, the optimal available member(s) of each breast cancer kindred attending our clinic was tested for BRCA mutations. Women in families without a demonstrable BRCA mutation were subjected to annual mammography. BRCA mutations were demonstrated in 496/2,118 (23 %) breast cancer kindreds. In families without a demonstrable BRCA mutation, a total of 3,161 healthy women aged 25–59 years were prospectively followed for 24,808 observation years. Sixty-four cancers were observed, compared to 34.0 expected (p < 0.01), arriving at a 7.9 % cumulative risk at age 60 compared to 4.0 % in the population [relative risk (RR) = 2.0]. Women with one mother or sister affected ≤50 years and with no other close relatives with breast cancer did not have increased risk (0 cancers observed and 0.6 expected at age 40, 11 cancers observed and 7.9 expected at age 60, p > 0.05). Excluding these, cumulative risk at 60 years was 8.8 % (RR = 2.2). The highest cumulative risk at 60 years was 11.4 %, found in families with two cases ≤55 years (RR = 2.8). In breast cancer kindreds without a demonstrable BRCA mutation, the risk for breast cancer in female first degree relatives was about twice the risk in the general population. Women with one early affected relative only did not have increased risk for early onset breast cancer, while those with more than one young affected relative had close to three times population risk.

High cumulative risk and clinical feature of intussusception in patients with Peutz-Jeghers syndrome

Objective To analyze the characteristics,risk and induced factors of intussusception in Peutz-Jeghers syndrome (PJS).Methods From March 2nd 2005 to May 25th 2013,a total of 130 patients with PJS were selected.The clinical data of patients were collected,which included gender,age,the diagnostic age of PJS,family history,the diagnostic age of intussusception,clinical features,location,treatment and the maximum diameter of polyps which caused intussusception.Kaplan-Meier was performed to analyze the cumulative risk of intussusception.Results Among 130 patients with PJS,90 cases had intussusception.The age when first time diagnosed was from four to 33,median age was 16.The cumulative risks of intussusception at 10,15,20,25 and 30 years were 12.308％ (16/130),31.538％(41/130),51.538％(67/130),64.615％(84/130) and 66.923％(87/130).There was no significant difference in the cumulative risk of intussusception between male and female; with family history and no family history (both P＞0.05).A total of 131 intussusception happened in 90 patients,of which diagnosed by surgery,imaging examination and history reviewer was 125,four and two times,respectively.The initial symptom of 111 times of intussusception was acute abdomen and 15 were abdominal pain and vomiting.The left five intussusception was found by regular:examination.One hundred and fifteen intussusception was in small intestine and 16 in colon.There was 127,three and one time treated with surgery,conservative treatment,endoscopic therapy (dual airbags intestinal endoscopic polypectomy),respectively.The maximum diameter of polyps which caused intussusception was from 15 to 70 mm,average 40 mm.Conclusions Intussusception of patients with PJS is at young age and with a high cumulative risk.Intussusception is generally caused by diameter over 15 mm polyps. Key words: Peutz-Jeghers syndrome; Intussusception; Endoscopy, gastrointestinal; Intestine,small; Intestinal polyps

Is Resilience Only Skin Deep?

Many African American youth may develop high levels of allostatic load, a measure of physiological wear and tear on the body, by developing psychosocial competence under conditions of high risk related to socioeconomic status (SES). The current study was designed to test this hypothesis, which is based on John Henryism theory. In a representative sample of 489 African American youth living in the rural South, cumulative SES-related risks and teacher-reported competence were assessed at ages 11 to 13; depressive symptoms, externalizing behavior, and allostatic load were assessed at age 19. The data revealed that rural African American preadolescents who evinced high psychosocial competence under conditions of high cumulative SES-related risk displayed low levels of adjustment problems along with high allostatic load at age 19. These results suggest that, for many rural African Americans, resilience may indeed be only “skin deep.”