Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics ...of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.
In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. ...Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new “basket” clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on 18F2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.
Bloodstream infections (BSI) and Clostridium difficile infections (CDI) in pediatric oncology/hematology/bone marrow transplant (BMT) populations are associated with significant morbidity and ...mortality. The objective of this study was to explore possible associations between altered microbiome composition and the occurrence of BSI and CDI in a cohort of pediatric oncology patients. Stool samples were collected from all patients admitted to the pediatric oncology floor from Oct.-Dec. 2012. Bacterial profiles from patient stools were determined by bacterial 16S rRNA gene profiling. Differences in overall microbiome composition were assessed by a permutation-based multivariate analysis of variance test, while differences in the relative abundances of specific taxa were assessed by Kruskal-Wallis tests. At admission, 9 of 42 patients (21%) were colonized with C. difficile, while 6 of 42 (14%) subsequently developed a CDI. Furthermore, 3 patients (7%) previously had a BSI and 6 patients (14%) subsequently developed a BSI. Differences in overall microbiome composition were significantly associated with disease type (p = 0.0086), chemotherapy treatment (p = 0.018), BSI following admission from any cause (p < 0.0001) or suspected gastrointestinal organisms (p = 0.00043). No differences in baseline microbiota were observed between individuals who did or did not subsequently develop C. difficile infection. Additionally, multiple bacterial groups varied significantly between subjects with post-admission BSI compared with no BSI. Our results suggest that differences in gut microbiota not only are associated with type of cancer and chemotherapy, but may also be predictive of subsequent bloodstream infection.
Infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) have a poor prognosis. KMT2A-r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i) lestaurtinib potentiates ...chemotherapy-induced cytotoxicity in preclinical models. Children's Oncology Group (COG) AALL0631 tested whether adding lestaurtinib to post-induction chemotherapy improved event-free survival (EFS). After chemotherapy induction, KMT2A-r infants received either chemotherapy only or chemotherapy plus lestaurtinib. Correlative assays included FLT3i plasma pharmacodynamics (PD), which categorized patients as inhibited or uninhibited, and FLT3i ex vivo sensitivity (EVS), which categorized leukemic blasts as sensitive or resistant. There was no difference in 3-year EFS between patients treated with chemotherapy plus lestaurtinib (n = 67, 36 ± 6%) vs. chemotherapy only (n = 54, 39 ± 7%, p = 0.67). However, for the lestaurtinib-treated patients, FLT3i PD and FLT3i EVS significantly correlated with EFS. For FLT3i PD, EFS for inhibited/uninhibited was 59 ± 10%/28 ± 7% (p = 0.009) and for FLTi EVS, EFS for sensitive/resistant was 52 ± 8%/5 ± 5% (p < 0.001). Seventeen patients were both inhibited and sensitive, with an EFS of 88 ± 8%. Adding lestaurtinib did not improve EFS overall, but patients achieving potent FLT3 inhibition and those whose leukemia blasts were sensitive FLT3-inhibition ex vivo did benefit from the addition of lestaurtinib. Patient selection and PD-guided dose escalation may enhance the efficacy of FLT3 inhibition for KMT2A-r infant ALL.
The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and ...cardiovascular events and mortality in patients with stable coronary heart disease.
The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycin group as replication sample: n = 1998, n = 1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomes n = 1204, n = 1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs.
Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05–1.19, p < 0.001, replication; HR 1.14, 95% CI 1.07–1.21, p < 0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events.
Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established.
•Cathepsin B and S are lysosomal proteins implicated in the atherosclerotic process.•The CLARICOR trial studied the effect of clarithromycin on cardiovascular mortality.•In this 10 year-follow up, Cathepsin B was associated with cardiovascular mortality.•Cathepsin S was not associated with cardiovascular mortality.
To ascertain parents' and physicians' assessments of quality of end-of-life care for children with cancer and to determine factors associated with high-quality care as perceived by parents and ...physicians.
A survey was conducted between 1997 and 2001 of 144 parents of children who received treatment at the Dana-Farber Cancer Institute and Children's Hospital (Boston, MA) or Children's Hospitals and Clinics of St Paul and Minneapolis, MN, between 1990 and 1999 (65% of those located and eligible) and 52 pediatric oncologists.
In multivariable models, higher parent ratings of physician care were associated with physicians giving clear information about what to expect in the end-of-life period (odds ratio OR = 19.90, P = .02), communicating with care and sensitivity (OR = 7.67, P < .01), communicating directly with the child when appropriate (OR = 11.18, P < .01), and preparing the parent for circumstances surrounding the child's death (OR = 4.84, P = .03). Parent reports of the child's pain and suffering were not significant correlates of parental ratings of care (P = .93 and .35, respectively). Oncologists' ratings of care were inversely associated with the parent's report of the child's experience of pain (OR = 0.15, P = .01) and more than 10 hospital days in the last month of life (OR = 0.24, P < .01). Parent-rated communication factors were not correlates of oncologist-rated care. No association was found between parent and physician care ratings (P = .88).
For parents of children who die of cancer, doctor-patient communication is the principal determinant of high-quality physician care. In contrast, physicians' care ratings depend on biomedical rather than relational aspects of care.
Background The inflammatory biomarker YKL-40 has previously been studied as a potential risk marker in cardiovascular disease. We aimed to assess the prognostic reclassification potential of serum ...YKL-40 in patients with stable coronary artery disease. Methods and Results The main study population was the placebo group of the CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) trial. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. We used Cox proportional hazards regression models adjusted for C-reactive protein level and baseline cardiovascular risk factors. Improvement in prediction by adding serum YKL-40 to the risk factors was calculated using the Cox-Breslow method and c-statistic. A total of 2200 patients were randomized to placebo, with a follow-up duration of 10 years. YKL-40 was associated with an increased risk of the composite outcome (hazard ratio per unit increase in (YKL-40) 1.13, 95% CI 1.03-1.24,
=0.013) and all-cause mortality (hazard ratio 1.32, 95% CI 1.17-1.49,
<0.0001). Considering whether a composite-outcome event was more likely to have, or not have, occurred to date, we found 68.4% of such predictions to be correct when based on the standard predictors, and 68.5% when serum YKL-40 was added as a predictor. Equivalent results were obtained with c-statistics. Conclusions Higher serum YKL-40 was independently associated with an increased risk of adverse cardiovascular outcomes and mortality. Addition of YKL-40 did not improve risk prediction in patients with stable coronary artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00121550.
Elevated circulating levels of osteoprotegerin (OPG) are known to add to the prediction of cardiovascular mortality. Our objective was to clarify the long-term risk associated with serum OPG and the ...possible influence of diabetes and statins on OPG levels in patients with stable coronary artery disease (CAD).
We assessed the placebo-treated group (n = 1998) from the CLARICOR trial (NCT00121550), a cohort with stable CAD. At entry, 15% of the participants had diabetes and 41% received statins. Serum OPG levels were measured in blood drawn at randomization. Participants were followed through public registers for 10 years.
OPG levels correlated positively with diabetes status, age, CRP and female sex, but negatively with the use of statins. CAD participants with diabetes had significantly elevated serum OPG levels compared to participants without diabetes, p < 0.0001. The participants without diabetes treated with statins presented with significantly lower serum OPG levels than the corresponding non-statin-users (p < 0.0001). However, statin use showed no association with OPG levels in the participants with diabetes. High OPG levels at entry showed long-term associations with all-cause mortality and cardiovascular events (hazard ratio associated with factor 10 OPG increase 15.9 (95% CI 11.0–22.9) and 6.38 (4.60–8.90), p = 0.0001, even after adjustment for standard predictors (3.16 (1.90–5.25) and 2.29 (1.53–3.44), p < 0.0001).
Circulating OPG holds long-term independent predictive ability for all-cause mortality and cardiovascular events in CAD participants. OPG levels were associated with diabetes, age, and female sex and statin treatment was associated with lower OPG levels in the absence of diabetes.
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•High serum osteoprotegerin (OPG) predicts mortality and cardiovascular events in coronary artery disease (CAD) patients a decade ahead•Serum OPG levels were elevated in participants with diabetes vs without diabetes•Statin users without diabetes presented with lower OPG levels than non-statin users
In 1998, the American Society of Clinical Oncology (ASCO) surveyed its membership to assess the attitudes, practices, and challenges associated with end-of-life care of patients with cancer. In this ...report, we summarize the responses of pediatric oncologists and the implications for care of children dying from cancer.
The survey consisted of 118 questions, covering eight categories. All ASCO members in the United States, Canada, and the United Kingdom were mailed a survey, which was completed by 228 pediatric oncologists. Predictors of particular attitudes and practices were identified using stepwise logistic regression analysis. Potential predictors were age, sex, religious affiliation, importance of religious beliefs, recent death of a relative, specialty, type of practice (rural or urban, academic or nonacademic), amount of time spent in patient care, number of new patients in the past 6 months, and number of patients who died in the past year.
Pediatric oncologists reported a lack of formal courses in pediatric palliative care, a strikingly high reliance on trial and error in learning to care for dying children, and a need for strong role models in this area. The lack of an accessible palliative care team or pain service was often identified as a barrier to good care. Communication difficulties exist between parents and oncologists, especially regarding the shift to end-of-life care and adequate pain control.
Pediatric oncologists are working to integrate symptom control, psychosocial support, and palliative care into the routine care of the seriously ill child, although barriers exist that make such comprehensive care a challenge.
Physical activity studies often utilize wearable devices to measure participants' habitual activity levels by averaging values across several valid observation days. These studies face competing ...demands-available resources and the burden to study participants must be balanced with the goal to obtain reliable measurements of a person's longer-term average. Information about the number of valid observation days required to reliably measure targeted metrics of habitual activity is required to inform study design.
To date, the number of days required to achieve a desired level of aggregate long-term reliability (typically 0.80) has often been estimated by applying the Spearman-Brown Prophecy formula to short-term test-retest reliability data from studies with single, relatively brief observation windows. Our work, in contrast, utilizes a resampling-based approach to quantify the long-term test-retest reliability of aggregate measures of activity in a cohort of 79 participants who were asked to wear a FitBit Flex every day for approximately one year.
The conventional approach can produce reliability estimates that substantially overestimate the actual test-retest reliability. Six or more valid days of observation for each participant appear necessary to obtain 0.80 reliability for the average amount of time spent in light physical activity; 8 and 10 valid days are needed for sedentary time and moderate/vigorous activity respectively.
Protocols that result in 7-10 valid observation days for each participant may be needed to obtain reliable measurements of key physical activity metrics.
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