Background
The objective of this study was to examine long‐term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane‐containing clinical trials.
Methods
P9404 (acute ...lymphoblastic leukemia/lymphoma ALL), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana‐Farber Cancer Institute 95‐01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow‐up events were assessed with cumulative incidence, Cox regression, and Fine‐Gray methods.
Results
In randomized trials (cumulative prescribed doxorubicin dose, 100‐360 mg/m2; median follow‐up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio HR, 0.84; 95% confidence interval CI, 0.63‐1.13), second cancers (HR, 1.19; 95% CI, 0.62‐2.30), all‐cause mortality (HR, 1.07; 95% CI, 0.78‐1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41‐5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450‐600 mg/m2; median follow‐up, 16.6‐18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20‐year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m2) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35).
Conclusions
Dexrazoxane did not appear to adversely affect long‐term mortality, event‐free survival, or second cancer risk.
Extended follow‐up from pediatric dexrazoxane‐containing trials suggested no adverse impact of dexrazoxane on all‐cause mortality or second cancer risk. Dexrazoxane was associated with a potential reduction in serious cardiovascular outcomes.
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Adult survivors of childhood cancer are at risk for cardiovascular events.
In this study, we sought to determine the risk for mortality after a major cardiovascular event among childhood cancer ...survivors compared with noncancer populations.
All-cause and cardiovascular cause-specific mortality risks after heart failure (HF), coronary artery disease (CAD), or stroke were compared among survivors and siblings in the Childhood Cancer Survivor Study (CCSS) and participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Cox proportional hazard regression models were used to estimate HRs and 95% CIs between groups, adjusted for demographic and clinical factors.
Among 25,658 childhood cancer survivors (median age at diagnosis 7 years, median age at follow-up or death 38 years) and 5,051 siblings, 1,780 survivors and 91 siblings had a cardiovascular event. After HF, CAD, and stroke, 10-year all-cause mortalities were 30% (95% CI: 26%-33%), 36% (95% CI: 31%-40%), and 29% (95% CI: 24%-33%), respectively, among survivors vs 14% (95% CI: 0%-25%), 14% (95% CI: 2%-25%), and 4% (95% CI: 0%-11%) among siblings. All-cause mortality risks among childhood cancer survivors were increased after HF (HR: 7.32; 95% CI: 2.56-20.89), CAD (HR: 5.54; 95% CI: 2.37-12.93), and stroke (HR: 3.57; 95% CI: 1.12-11.37). CAD-specific mortality risk was increased (HR: 3.70; 95% CI: 1.05-13.02). Among 5,114 CARDIA participants, 345 had a major event. Although CARDIA participants were on average decades older at events (median age 57 years vs 31 years), mortality risks were similar, except that all-cause mortality after CAD was significantly increased among childhood cancer survivors (HR: 1.85; 95% CI: 1.16-2.95).
Survivors of childhood cancer represent a population at high risk for mortality after major cardiovascular events.
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Testicular germ cell tumors (TGCT) have been expected to have a strong underlying genetic component. We conducted a genome-wide scan among 277 TGCT cases and 919 controls and found that seven markers ...at 12p22 within KITLG (c-KIT ligand) reached genome-wide significance (P < 5.0 × 10−8 in discovery). In independent replication, TGCT risk was increased threefold per copy of the major allele at rs3782179 and rs4474514 (OR = 3.08, 95% CI = 2.29-4.13; OR = 3.07, 95% CI = 2.29-4.13, respectively). We found associations with rs4324715 and rs6897876 at 5q31.3 near SPRY4 (sprouty 4; P < 5.0 × 10−6 in discovery). In independent replication, risk of TGCT was increased nearly 40% per copy of the major allele (OR = 1.37, 95% CI = 1.14-1.64; OR = 1.39, 95% CI = 1.16-1.66, respectively). All of the genotypes were associated with both seminoma and nonseminoma TGCT subtypes. These results demonstrate that common genetic variants affect TGCT risk and implicate KITLG and SPRY4 as genes involved in TGCT susceptibility.
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For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking.
Within the Children's Oncology Group and the ...Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m
across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m
ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status.
From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m
). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% 95% CI, 0.3 to 2.5) and ejection fraction (absolute difference, +1.6% 95% CI, 0.0 to 3.2), and lower myocardial stress per B-type natriuretic peptide (-6.7 pg/mL 95% CI, -10.6 to -2.8). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 95% CI, 0.07 to 0.81). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m
.
Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.
Little is known about the etiologic profile of triple-negative breast cancer (negative for estrogen receptor/progesterone
receptor/human epidermal growth factor), a breast cancer subtype associated ...with high mortality and inadequate therapeutic
options. We undertook this study to assess the risk for triple-negative breast cancer among women 45 years of age and younger
in relation to demographic/lifestyle factors, reproductive history, and oral contraceptive use. Study participants were ascertained
in two previous population-based, case-control studies. Eligible cases included all primary invasive breast cancers among
women ages 20 to 45 years in the Seattle–Puget Sound area, diagnosed between January 1983 and December 1992, for whom complete
data was obtained for estrogen receptor, progesterone receptor, and human epidermal growth factor status ( n = 897; including n = 187 triple-negative breast cancer cases). Controls were age matched and ascertained via random digit dialing. Oral contraceptive
use ≥1 year was associated with a 2.5-fold increased risk for triple-negative breast cancer (95% confidence interval, 1.4-4.3)
and no significantly increased risk for non-triple-negative breast cancer ( P heterogeneity = 0.008). Furthermore, the risk among oral contraceptive users conferred by longer oral contraceptive duration and by more
recent use was significantly greater for triple-negative breast cancer than non-triple-negative breast cancer ( P heterogeneity = 0.02 and 0.01, respectively). Among women ≤40 years, the relative risk for triple-negative breast cancer associated with
oral contraceptive use ≥1 year was 4.2 (95% confidence interval, 1.9-9.3), whereas there was no significantly increased risk
with oral contraceptive use for non-triple-negative breast cancer among women ≤40 years, nor for triple-negative breast cancer
or non-triple-negative breast cancer among women 41 to 45 years of age. In conclusion, significant heterogeneity exists for
the association of oral contraceptive use and breast cancer risk between triple-negative breast cancer and non-triple-negative
breast cancer among young women, lending support to a distinct etiology. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1157–66)
Childhood cancer survivors are at risk for cardiovascular disease. We assessed the burden of potentially modifiable cardiometabolic risk factors (CRF) among survivors compared with population-matched ...controls.
Survivors previously enrolled on Pediatric Oncology Group protocols 9404, 9425, 9426, 9754, and Dana-Farber Cancer Institute 95-01 from 1996 to 2001 with acute lymphoblastic leukemia/lymphoma, Hodgkin lymphoma, or osteosarcoma were prospectively assessed for the prevalence of CRFs and compared with an age, sex, and race/ethnicity-matched 2013 National Health and Nutrition Examination Survey (NHANES) population. We estimated future predicted cardiovascular risk based on general population (e.g., Framingham) and Childhood Cancer Survivor Study (CCSS) models.
Compared with NHANES (n = 584), survivors n = 164; 44.5% female, median age 28 years (range, 16-38 years); median 17.4 years (range, 13-22 years) since cancer diagnosis; median doxorubicin dose 300 mg/m2; 30.5% chest radiation had similar rates of obesity, diabetes, and dyslipidemia, but more prehypertension/hypertension (38.4% vs. 30.1%, P = 0.044). Survivors had fewer metabolic syndrome features compared with NHANES (≥2 features: 26.7% vs. 55.9%; P < 0.001). Survivors were more physically active and smoked tobacco less (both P < 0.0001). Therefore, general population cardiovascular risk scores were lower for survivors versus NHANES. However, with CCSS models, 30.5% of survivors were at moderate risk of ischemic heart disease, and >95% at moderate/high risk for heart failure, with a 9% to 12% predicted incidence of these conditions by age 50 years.
Childhood cancer survivors exhibited similar or better cardiometabolic and lifestyle profiles compared with NHANES, but nonetheless are at risk for future clinically significant cardiovascular disease.
Further strategies supporting optimal CRF control are warranted in survivors. See related commentary by Mulrooney, p. 515.
Given concerns that dexrazoxane may reduce treatment efficacy, induce second cancers, and thus compromise overall survival among children, we examined long-term overall and cause-specific mortality ...and disease relapse rates from three randomized clinical trials.
Children's Oncology Group trials P9404 (T-cell acute lymphoblastic leukemia/lymphoma; n = 537), P9425 (intermediate/high-risk Hodgkin lymphoma; n = 216), and P9426 (low-risk Hodgkin lymphoma; n = 255) were conducted between 1996 and 2001. Each trial randomly assigned patients to doxorubicin with or without dexrazoxane. The dexrazoxane:doxorubicin dose ratio was 10:1, and the cumulative protocol-specified doxorubicin dose was 100 to 360 mg/m(2). Dexrazoxane was given as an intravenous bolus before each doxorubicin dose. Data from all three trials were linked with the National Death Index to determine overall and cause-specific mortality by dexrazoxane status.
Among 1,008 patients (507 received dexrazoxane) with a median follow-up of 12.6 years (range, 0 to 15.5 years), 132 died (67 received dexrazoxane). Overall mortality did not vary by dexrazoxane status (12.8% with dexrazoxane at 10 years v 12.2% without; hazard ratio HR, 1.03; 95% CI, 0.73 to 1.45). Findings were similar when each trial was examined separately. Dexrazoxane also was not significantly associated with differential causes of death. The original cancer caused 76.5% of all deaths (HR, 0.90; 95% CI, 0.61 to 1.32) followed by second cancers (13.6% of deaths; HR, 1.24; 95% CI, 0.49 to 3.15). Specifically, dexrazoxane was not associated with deaths from acute myeloid leukemia/myelodysplasia or cardiovascular events.
Among pediatric patients with leukemia or lymphoma, after extended follow-up, dexrazoxane use did not seem to compromise long-term survival.
The presence of a congenital anomaly is associated with increased childhood cancer risk, likely due to large effects of Down syndrome and chromosomal anomalies for leukemia. Less is known about ...associations with presence of non-chromosomal anomalies.
Records of children diagnosed with cancer at <20 years of age during 1984-2013 in Washington State cancer registries were linked to their birth certificates (N = 4,105). A comparison group of children born in the same years was identified. Congenital anomalies were assessed from birth records and diagnosis codes in linked hospital discharge data. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for cancer, and for specific cancer types in relation to the presence of any anomaly and specific anomalies.
Having any congenital anomaly was associated with an increased risk of childhood cancer (OR: 1.46, 95% CI 1.28-1.65). Non-chromosomal anomalies were also associated with increased childhood cancer risk overall (OR: 1.35; 95% CI: 1.18-1.54), and with increased risk of several cancer types, including neuroblastoma, renal, hepatoblastoma, soft-tissue sarcoma, and germ cell tumors. Increasing number of non-chromosomal anomalies was associated with a stronger risk of childhood cancer (OR for 3+ anomalies: 3.11, 95% CI: 1.54-6.11). Although central nervous system (CNS) anomalies were associated with CNS tumors (OR: 6.05, 95% CI 2.75-13.27), there was no strong evidence of other non-chromosomal anomalies being specifically associated with cancer occurring in the same organ system or anatomic location.
Non-chromosomal anomalies increased risk of several cancer types. Additionally, we found that increasing number of non-chromosomal anomalies was associated with a stronger risk of cancer. Pooling similar data from many regions would increase power to identify specific associations in order to inform molecular studies examining possible common developmental pathways in the etiologies of birth defects and cancer.
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Objective
To compare obstetric/birth outcomes and rehospitalization among women with and without rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and their infants.
Methods
This ...population‐based retrospective cohort study identified women with RA (n = 1,223) and SLE (n = 1,354) and unexposed women with singleton births 1987–2014 in Washington State in linked vital hospital discharge records. Outcomes, including cause‐specific hospitalizations <2 years postpartum, were compared by estimating adjusted relative risks (RRs) and cause‐specific rehospitalization hazard ratios (HRs) with 95% confidence intervals (95% CIs).
Results
We observed increased risks of several adverse outcomes; RRs were often greatest for SLE. Women with RA/SLE more often required rehospitalization, most notably at <6 months postpartum (RA: 4% versus 2%; RR 2.22 95% CI 1.62–3.04; SLE: 6% versus 2%; RR 2.78 95% CI 2.15–3.59). Maternal postpartum rehospitalization was greatest for musculoskeletal conditions (RA: HR 19.1 95% CI 13.6–26.8; SLE: HR 29.8 95% CI 22.1–40.1). Infants of women with SLE more often had malformations (9% versus 6%; RR 1.46 95% CI 1.21–1.75), and increased mortality at <2 years (RR 2.11 95% CI 1.21–3.67). Infants of women with SLE also experienced more frequent rehospitalizations in their first year of life.
Conclusion
Women with RA or SLE and their infants experienced adverse outcomes, particularly infants of women with SLE. Maternal/infant rehospitalization was more common; most marked in the early months postpartum. Close follow‐up during these time periods is crucial to minimize adverse outcomes.
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10.
In vitro generation of long-lived human plasma cells Cocco, Mario; Stephenson, Sophie; Care, Matthew A ...
The Journal of immunology (1950),
2012-Dec-15, 2012-12-15, 20121215, Volume:
189, Issue:
12
Journal Article
Peer reviewed
Open access
Plasma cells (PCs), the terminal effectors of humoral immunity, are short-lived unless supported by niche environments in which they may persist for years. No model system has linked B cell ...activation with niche function to allow the in vitro generation of long-lived PCs. Thus, the full trajectory of B cell terminal differentiation has yet to be investigated in vitro. In this article, we describe a robust model for the generation of polyclonal long-lived human PCs from peripheral blood B cells. After a proliferative plasmablast phase, PCs persist in the absence of cell division, with viability limited only by elective culture termination. Conservative predictions for PC life expectancy are 300 d, but with the potential for significantly longer life spans for some cells. These long-lived PCs are preferentially derived from memory B cells, and acquire a CD138(high) phenotype analogous to that of human bone marrow PCs. Analysis of gene expression across the system defines clusters of genes with related dynamics and linked functional characteristics. Importantly, genes in these differentiation clusters demonstrate a similar overall pattern of expression for in vitro and ex vivo PCs. In vitro PCs are fully reprogrammed to a secretory state and are adapted to their secretory load, maintaining IgG secretion of 120 pg/cell/day in the absence of XBP1 mRNA splicing. By establishing a set of conditions sufficient to allow the development and persistence of mature human PCs in vitro, to our knowledge, we provide the first platform with which to sequentially explore and manipulate each stage of human PC differentiation.
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