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1.  Irregular vascular pattern by contrast‐enhanced ultrasonography and high serum Lens culinaris agglutinin‐reactive fraction of alpha‐fetoprotein level predict poor outcome after successful radiofrequency ablation in patients with early‐stage hepatocellular carcinoma 
Cancer Medicine  2016;5(11):3111-3120.
Abstract
Radiofrequency ablation (RFA) is considered the most effective treatment for early‐stage hepatocellular carcinoma (HCC) patients unsuitable for resection. However, poor outcome after RFA has occasionally been reported worldwide. To predict such an outcome, we investigated imaging findings using contrast‐enhanced ultrasonography (CEUS) with Sonazoid and serum tumor markers before RFA. This study included 176 early‐stage HCC patients who had initially achieved successful RFA. Patients were examined using CEUS; their levels of alpha‐fetoprotein (AFP), Lens culinaris agglutinin‐reactive fraction of AFP (AFP‐L3), and des‐gamma‐carboxy prothrombin before RFA were measured. Sonazoid provided parenchyma‐specific contrast imaging and facilitated tumor vascular architecture imaging through maximum intensity projection (MIP). Kaplan–Meier analysis examined cumulative rates of local tumor progression, intrasubsegmental recurrence, and survival; factors associated with these were determined with Cox proportional hazards analysis. Local tumor progression (n = 15), intrasubsegmental recurrence (n = 46), and death (n = 18) were observed. Irregular pattern in MIP classification and serum AFP‐L3 level (>10%) before RFA were identified as independent risk factors for local tumor progression and intrasubsegmental recurrence. These two factors were independently associated with poor survival after RFA (irregular pattern in MIP: hazard ratio, (HR) = 8.26; 95% confidence interval, (CI) = 2.24–30.3; P = 0.002 and AFP‐L3 > 10%: HR = 2.94; 95% CI = 1.09–7.94; P = 0.033). Irregular MIP pattern by CEUS and high level of serum AFP‐L3 were independent risk factors for poor outcome after successful RFA. The Patients with these findings should be considered as special high‐risk group in early‐stage HCC.
doi:10.1002/cam4.932
PMCID: PMC5119966  PMID: 27748052
Alpha‐fetoprotein; contrast‐enhanced ultrasonography; hepatocellular carcinoma; intrasubsegmental recurrence; poor survival; radiofrequency ablation
2.  Novel Pretreatment Scoring Incorporating C-reactive Protein to Predict Overall Survival in Advanced Hepatocellular Carcinoma with Sorafenib Treatment 
Liver Cancer  2016;5(4):257-268.
Objectives
This study aimed to build a prediction score of prognosis for patients with advanced hepatocellular carcinoma (HCC) after sorafenib treatment.
Methods
A total of 165 patients with advanced HCC who were treated with sorafenib were analyzed. Readily available baseline factors were used to establish a scoring system for the prediction of survival.
Results
The median survival time (MST) was 14.2 months. The independent prognostic factors were C-reactive protein (CRP) <1.0 mg/dL [hazard ratio (HR) =0.51], albumin >3.5 g/dL (HR =0.55), alpha-fetoprotein <200 ng/mL (HR =0.45), and a lack of major vascular invasion (HR =0.39). Each of these factors had a score of 1, and after classifying the patients into five groups, the total scores ranged from 0 to 4. Higher scores were linked to significantly longer survival (p<0.0001). Twenty-nine patients (17.6%) with a score of 4 had a MST as long as 36.5 months, whereas MST was as short as 2.4 and 3.7 months for seven (4.2%) and 22 (13.3%) patients with scores of 0 and 1, respectively.
Conclusions
A novel prognostic scoring system, which includes the CRP level, has the ability to stratify the prognosis of patients with advanced stage HCC after treatment with sorafenib.
doi:10.1159/000449337
PMCID: PMC5075810  PMID: 27781198
Hepatocellular carcinoma; Prognostic prediction; Systemic chemotherapy
3.  Intestinal Obstruction in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2015;33(26):2893-2900.
Purpose
For adult survivors of childhood cancer, knowledge about the long-term risk of intestinal obstruction from surgery, chemotherapy, and radiotherapy is limited.
Methods
Intestinal obstruction requiring surgery (IOS) occurring 5 or more years after cancer diagnosis was evaluated in 12,316 5-year survivors in the Childhood Cancer Survivor Study (2,002 with and 10,314 without abdominopelvic tumors) and 4,023 sibling participants. Cumulative incidence of IOS was calculated with second malignant neoplasm, late recurrence, and death as competing risks. Using piecewise exponential models, we assessed the associations of clinical and demographic factors with rate of IOS.
Results
Late IOS was reported by 165 survivors (median age at IOS, 19 years; range, 5 to 50 years; median time from diagnosis to IOS, 13 years) and 14 siblings. The cumulative incidence of late IOS at 35 years was 5.8% (95% CI, 4.4% to 7.3%) among survivors with abdominopelvic tumors, 1.0% (95% CI, 0.7% to 1.4%) among those without abdominopelvic tumors, and 0.3% (95% CI, 0.1% to 0.5%) among siblings. Among survivors, abdominopelvic tumor (adjusted rate ratio [ARR], 3.6; 95% CI, 1.9 to 6.8; P < .001) and abdominal/pelvic radiotherapy within 5 years of cancer diagnosis (ARR, 2.4; 95% CI, 1.6 to 3.7; P < .001) increased the rate of late IOS, adjusting for diagnosis year; sex; race/ethnicity; age at diagnosis; age during follow-up (as natural cubic spline); cancer type; and chemotherapy, radiotherapy, and surgery within 5 years of cancer diagnosis. Developing late IOS increased subsequent mortality among survivors (ARR, 1.8; 95% CI, 1.1 to 2.9; P = .016), adjusting for the same factors.
Conclusion
The long-term risk of IOS and its association with subsequent mortality underscore the need to promote awareness of this complication among patients and providers.
doi:10.1200/JCO.2015.61.5070
PMCID: PMC4554750  PMID: 26261256
4.  Reduction in Late Mortality among Five-Year Survivors of Childhood Cancer 
The New England journal of medicine  2016;374(9):833-842.
Background
Previously, eighteen percent of childhood cancer patients who survived five years died within the subsequent 25 years. In recent decades, cancer treatment regimens have been modified with the goal of reducing risk for life-threatening late effects.
Methods
Late mortality was evaluated in 34,033 five-year survivors of childhood cancer (diagnosed <21 years of age from 1970-1999, median follow-up 21 years, range 5-38). Demographic and disease factors associated with mortality due to health-related causes, which exclude recurrence/progression of the original cancer but include deaths that reflect late effects of cancer therapy, were evaluated using cumulative incidence and piecewise exponential models estimating relative rates (RRs) and 95% confidence intervals (CI).
Results
1,618 (41%) of the 3,958 deaths were attributable to health-related causes, including 746 subsequent neoplasm, 241 cardiac, and 137 pulmonary deaths. Reduction in 15-year mortality was observed for all-cause (12.4% to 6.0%, P for trend <0.001) and health-related mortality (3.5% to 2.1%, P for trend <0.001), attributable to reductions in subsequent neoplasm (P<0.001), cardiac (P<0.001) and pulmonary death (P<0.001). Changes in therapy by decade included reduced rates of: cranial radiotherapy for acute lymphoblastic leukemia (1970s 85%, 1980s 51%, 1990s 19%), abdominal radiotherapy for Wilms’ tumor (78%, 53%, 43%), chest radiotherapy for Hodgkin's lymphoma (87%, 79%, 61%), and anthracycline exposure. Reduction in treatment exposure was associated with reduced late mortality among lymphoblastic leukemia and Wilms’ tumor survivors.
Conclusion
The strategy of lowering therapeutic exposure has successfully translated to an observed decline in late mortality among 5-year survivors of childhood cancer.
doi:10.1056/NEJMoa1510795
PMCID: PMC4786452  PMID: 26761625
Pediatric; Cancer; Survivor; Mortality
5.  A Candidate-Pathway Approach to Identify Gene-Environment Interactions: Analyses of Colon Cancer Risk and Survival 
Background:
Genetic association studies have traditionally focused on associations between individual single nucleotide polymorphisms (SNPs) and disease. Standard analysis ignores interactions between multiple SNPs and environmental exposures explaining a small portion of disease heritability: the often-cited issue of “missing heritability.”
Methods:
We present a novel three-step analytic framework for modeling gene-environment interactions (GEIs) between an angiogenesis candidate-gene pathway and three lifestyle exposures (dietary protein, smoking, and alcohol consumption) on colon cancer risk and survival. Logic regression was used to summarize the gene-pathway effects, and GEIs were modeled using logistic regression and Cox proportional hazards models. We analyzed data from 1541 colon cancer case patients and 1934 control subjects in the Diet, Activity and Lifestyle as a Risk Factor for Colon Cancer Study.
Results:
We identified five statistically significant GEIs for colon cancer risk. For risk interaction, odds ratios (ORINT) and 95% confidence intervals (CIs) were FLT1(rs678714) and BMP4(rs17563) and smoking (ORINT = 1.64, 95% CI = 1.11 to 2.41 and ORINT = 1.60, 95% CI = 1.10 to 2.32, respectively); FLT1(rs2387632 OR rs9513070) and protein intake (ORINT = 1.69, 95% CI = 1.03 to 2.77); KDR(rs6838752) and TLR2(rs3804099) and alcohol (ORINT = 1.53, 95% CI = 1.10 to 2.13 and ORINT = 1.59, 95% CI = 1.05 to 2.38, respectively). Three GEIs between TNF, BMP1, and BMPR2 genes and the three exposures were statistically significant at the 5% level in relation to colon cancer survival but not after multiple-testing adjustment.
Conclusions:
Adopting a comprehensive biologically informed candidate-pathway approach identified GEI effects on colon cancer. Findings may have important implications for public health and personalized medicine targeting prevention and therapeutic strategies. Findings from this study need to be validated in other studies.
doi:10.1093/jnci/djv160
PMCID: PMC4651103  PMID: 26072521
6.  Evidence of Naturalized Stress-Tolerant Strains of Escherichia coli in Municipal Wastewater Treatment Plants 
Applied and Environmental Microbiology  2016;82(18):5505-5518.
ABSTRACT
Escherichia coli has been proposed to have two habitats—the intestines of mammals/birds and the nonhost environment. Our goal was to assess whether certain strains of E. coli have evolved toward adaptation and survival in wastewater. Raw sewage samples from different treatment plants were subjected to chlorine stress, and ∼59% of the surviving E. coli strains were found to contain a genetic insertion element (IS30) located within the uspC-flhDC intergenic region. The positional location of the IS30 element was not observed across a library of 845 E. coli isolates collected from various animal hosts or within GenBank or whole-genome reference databases for human and animal E. coli isolates (n = 1,177). Phylogenetics clustered the IS30 element-containing wastewater E. coli isolates into a distinct clade, and biomarker analysis revealed that these wastewater isolates contained a single nucleotide polymorphism (SNP) biomarker pattern that was specific for wastewater. These isolates belonged to phylogroup A, possessed generalized stress response (RpoS) activity, and carried the locus of heat resistance, features likely relevant to nonhost environmental survival. Isolates were screened for 28 virulence genes but carried only the fimH marker. Our data suggest that wastewater contains a naturalized resident population of E. coli. We developed an endpoint PCR targeting the IS30 element within the uspC-flhDC intergenic region, and all raw sewage samples (n = 21) were positive for this marker. Conversely, the prevalence of this marker in E. coli-positive surface and groundwater samples was low (≤5%). This simple PCR assay may represent a convenient microbial source-tracking tool for identification of water samples affected by municipal wastewater.
IMPORTANCE The results of this study demonstrate that some strains of E. coli appear to have evolved to become naturalized populations in the wastewater environment and possess a number of stress-related genetic elements likely important for survival in this nonhost environment. The presence of non-host-adapted strains in wastewater challenges our understanding of using E. coli as a microbial indicator of wastewater treatment performance, suggesting that the E. coli strains present in human and animal feces may be very different from those found in treated wastewater.
doi:10.1128/AEM.00143-16
PMCID: PMC5007776  PMID: 27371583
8.  Impact of aerobic exercise on levels of IL‐4 and IL‐10: results from two randomized intervention trials 
Cancer Medicine  2016;5(9):2385-2397.
Abstract
The mechanisms whereby regular exercise reduces chronic inflammation remain unclear. We investigated whether regular aerobic exercise alters basal levels of interleukin (IL)‐10 and IL‐4 in two randomized trials of physical activity. The Alberta Physical Activity and Breast Cancer Prevention Trial (ALPHA, n = 320) and the Breast Cancer and Exercise Trial in Alberta (BETA, n = 400) were two‐center, two‐armed randomized trials in inactive, healthy, postmenopausal women. Both trials included an exercise intervention prescribed five times/week and no dietary changes. In ALPHA, the exercise group was prescribed 225 min/week versus no activity in the controls. BETA examined dose‐response effects comparing 300 (HIGH) versus 150 (MODERATE) min/week. Plasma concentrations of IL‐10 and IL‐4 were measured at baseline, 6, and 12 months. Intention‐to‐treat (ITT) analysis was performed using linear mixed models adjusted for baseline biomarker concentrations. Circulating anti‐inflammatory cytokine levels decreased among all groups, with percent change ranging from −3.4% (controls) to −8.2% (HIGH) for IL‐4 and −1.6% (controls) to −7.5% (HIGH) for IL‐10. No significant group differences were found for IL‐4 (ALPHA P = 0.54; BETA P = 0.32) or IL‐10 (ALPHA P = 0.84; BETA P = 0.68). Some evidence for moderation of the effect of exercise by baseline characteristics was found for IL‐10 but not for IL‐4. Results from these two large randomized aerobic exercise intervention trials suggest that aerobic exercise does not alter IL‐10 or IL‐4 in a manner consistent with chronic disease and cancer prevention.
doi:10.1002/cam4.836
PMCID: PMC5055172  PMID: 27485297
Aerobic exercise; anti‐inflammatory markers; breast cancer; randomized controlled trial
9.  Identifying Predictors of Longitudinal Decline in the Level of Medical Care Received by Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Health Services Research  2015;50(4):1021-1042.
Objectives
Characterize longitudinal changes in the use of medical care in adult survivors of childhood cancer.
Data Sources
The Childhood Cancer Survivor Study, a retrospective cohort study of 5+ year survivors of childhood cancer.
Study Design
Medical care was assessed at entry into the cohort (baseline) and at most recent questionnaire completion. Care at each time point was classified as no care, general care, or survivor-focused care.
Data Collection
There were 6,176 eligible survivors. Multivariable models evaluated risk factors for reporting survivor-focused care or general medical care at baseline and no care at follow-up; and survivor-focused care at baseline and general care at follow-up.
Principal Findings
Males (RR, 2.3; 95 percent CI 1.8–2.9), earning <$20,000/year (RR, 1.6; 95 percent CI 1.2–2.3) or ≤high school education (RR, 2.5; 95 percent CI 1.6–3.8 and RR 2.0; 95 percent CI 1.5–2.7 for
Conclusions
While the incidence of late effects increases over time for survivors, the likelihood of receiving survivor-focused care decreases for vulnerable populations.
doi:10.1111/1475-6773.12282
PMCID: PMC4545345  PMID: 25600956
Childhood cancer survivors; health insurance; health care access; survivorship; delivery of health care
Cancer  2016;122(15):2426-2439.
By the middle of this century, racial/ethnic minority populations will collectively constitute 50% of the US population. This temporal shift in the racial/ethnic make-up of the US population demands a close look at the race/ethnicity-specific burden of morbidity and premature mortality among childhood cancer survivors. To optimize targeted long-term follow-up care, it is essential to understand whether the burden of morbidity borne by survivors of childhood cancer differs by race/ethnicity. This is challenging because the number of minority participants is often limited in current childhood cancer survivorship research, resulting in a paucity of race/ethnicity-specific recommendations and/or interventions. We show that while the overall childhood cancer incidence increased between 1973 and 2003, the mortality rate declined; however these changes did not differ appreciably by race/ethnicity. We speculate that any racial/ethnic differences in outcome are likely to be multifactorial, and draw upon data from the Childhood Cancer Survivor Study to illustrate the various contributors (socioeconomic characteristics, health behaviors and comorbidities) that could explain any observed differences in key treatment-related complications. Finally, we outline challenges in conducting race/ethnicity-specific childhood cancer survivorship research, showing that there are limited absolute numbers of children who are diagnosed and survive cancer in any one racial/ethnic minority population, precluding a rigorous evaluation of adverse events among specific primary cancer diagnoses and treatment exposure groups.
doi:10.1002/cncr.30072
PMCID: PMC4956492  PMID: 27253866
PLoS ONE  2016;11(4):e0154558.
Background & Aims
The fibrosis stage, which is evaluated by the distribution pattern of collagen fibers, is a major predictor for the development of hepatocellular carcinoma (HCC) for patients with hepatitis C. Meanwhile, the role of elastin fibers has not yet been elucidated. The present study was conducted to determine the significance of quantifying both collagen and elastin fibers.
Methods
We enrolled 189 consecutive patients with hepatitis C and advanced fibrosis. Using Elastica van Gieson-stained whole-slide images of pretreatment liver biopsies, collagen and elastin fibers were evaluated pixel by pixel (0.46 μm/pixel) using an automated computational method. Consequently, fiber amount and cumulative incidences of HCC within 3 years were analyzed.
Results
There was a significant correlation between collagen and elastin fibers, whereas variation in elastin fiber was greater than in collagen fiber. Both collagen fiber (p = 0.008) and elastin fiber (p < 0.001) were significantly correlated with F stage. In total, 30 patients developed HCC during follow-up. Patients who have higher elastin fiber (p = 0.002) in addition to higher collagen fiber (p = 0.05) showed significantly higher incidences of HCC. With regard to elastin fiber, this difference remained significant in F3 patients. Furthermore, for patients with a higher collagen fiber amount, higher elastin was a significant predictor for HCC development (p = 0.02).
Conclusions
Computational analysis is a novel technique for quantification of fibers with the added value of conventional staging. Elastin fiber is a predictor for the development of HCC independently of collagen fiber and F stage.
doi:10.1371/journal.pone.0154558
PMCID: PMC4851385  PMID: 27128435
American Journal of Epidemiology  2015;181(7):532-540.
Cumulative incidence has been widely used to estimate the cumulative probability of developing an event of interest by a given time, in the presence of competing risks. When it is of interest to measure the total burden of recurrent events in a population, however, the cumulative incidence method is not appropriate because it considers only the first occurrence of the event of interest for each individual in the analysis: Subsequent occurrences are not included. Here, we discuss a straightforward and intuitive method termed “mean cumulative count,” which reflects a summarization of all events that occur in the population by a given time, not just the first event for each subject. We explore the mathematical relationship between mean cumulative count and cumulative incidence. Detailed calculation of mean cumulative count is described by using a simple hypothetical example, and the computation code with an illustrative example is provided. Using follow-up data from January 1975 to August 2009 collected in the Childhood Cancer Survivor Study, we show applications of mean cumulative count and cumulative incidence for the outcome of subsequent neoplasms to demonstrate different but complementary information obtained from the 2 approaches and the specific utility of the former.
doi:10.1093/aje/kwu289
PMCID: PMC4371763  PMID: 25693770
cumulative incidence; disease burden; mean cumulative count; recurrent events
Cancer  2014;121(7):1108-1117.
Background
Long-term survivors of pediatric cancer are at risk for life-threatening late effects of their cancer. Previous studies have shown excesses in long-term mortality within high-risk groups defined by demographic and treatment characteristics.
Methods
To investigate conditional survival in a pediatric cancer population, we performed an analysis of conditional survival in the original Childhood Cancer Survivor Study (CCSS) cohort and the Surveillance, Epidemiology and End Results (SEER) database registry. The overall probability of death for patients in 5 years and 10 years after they survived 5, 10, 15, and 20 years since cancer diagnosis, and cause-specific death in 10 years for 5-year survivors were estimated using the cumulative incidence method.
Results
Among CCSS and SEER patients who were alive 5 years post cancer diagnosis, within each diagnosis group at least 92% are alive in the subsequent 5 years, except leukemia patients of whom only 88% of 5-year survivors remain alive in the subsequent 5 years. The probability of all-cause mortality in the next 10 years on patients who survived at least 5 years after diagnosis, was 8.8% in CCSS and 10.6% in SEER, approximately three quarter of which were due to neoplasms as causes of death.
Conclusion
The risk of death of pediatric cancer survivors in 10 years can vary between diagnosis groups by at most 12% even up to 20 years post diagnosis. This information is clinically important in counseling patients on their conditional survival, particularly when survivors are seen in long-term follow-up.
doi:10.1002/cncr.29170
PMCID: PMC4368489  PMID: 25557134
pediatric cancer; survivors; conditional survival; cause-specific mortality; cohort study
PLoS ONE  2016;11(2):e0149235.
Aim
For patients receiving endoscopic submucosal dissection (ESD), there is urgent need pertaining to the prevention of postoperative bleeding. We conducted a retrospective propensity score-matched study that evaluated whether pre-ESD gastric lavage prevents postoperative bleeding after ESD for gastric neoplasms.
Methods
From September 2002 to October 2015, the 760 consecutive patients receiving ESD for gastric neoplasm were enrolled and data regarding them were retrospectively analyzed. All patients received conventional preventive treatment against delayed bleeding after ESD, including the administration of proton pump inhibitor and preventive coagulation of visible vessels, at the end of the ESD procedure.
Results
Pre-ESD risk factors for postoperative bleeding included tumor size and no gastric lavage. Using multivariate analysis tumor size >2.0 cm (HR 2.90, 95% CI 1.65–5.10, p = 0.0002) and no gastric lavage (HR 3.20, 95% CI 1.13–9.11, p = 0.029) were found to be independent risk factors. Next, we evaluated the effect of gastric lavage on the prevention of post-ESD bleeding using a propensity score-matching method. A total of 284 subjects (142 per group) were selected. Adjusted odds ratio of gastric lavage for post-ESD bleeding was 0.25 (95% CI 0.071–0.886, p = 0.032).
Conclusion
Pretreatment gastric lavage reduced postoperative bleeding in patients receiving ESD for gastric neoplasm.
doi:10.1371/journal.pone.0149235
PMCID: PMC4752263  PMID: 26871449
Journal of Clinical Oncology  2014;33(5):394-402.
Purpose
To create clinically useful models that incorporate readily available demographic and cancer treatment characteristics to predict individual risk of heart failure among 5-year survivors of childhood cancer.
Patients and Methods
Survivors in the Childhood Cancer Survivor Study (CCSS) free of significant cardiovascular disease 5 years after cancer diagnosis (n = 13,060) were observed through age 40 years for the development of heart failure (ie, requiring medications or heart transplantation or leading to death). Siblings (n = 4,023) established the baseline population risk. An additional 3,421 survivors from Emma Children's Hospital (Amsterdam, the Netherlands), the National Wilms Tumor Study, and the St Jude Lifetime Cohort Study were used to validate the CCSS prediction models.
Results
Heart failure occurred in 285 CCSS participants. Risk scores based on selected exposures (sex, age at cancer diagnosis, and anthracycline and chest radiotherapy doses) achieved an area under the curve of 0.74 and concordance statistic of 0.76 at or through age 40 years. Validation cohort estimates ranged from 0.68 to 0.82. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups, corresponding to cumulative incidences of heart failure at age 40 years of 0.5% (95% CI, 0.2% to 0.8%), 2.4% (95% CI, 1.8% to 3.0%), and 11.7% (95% CI, 8.8% to 14.5%), respectively. In comparison, siblings had a cumulative incidence of 0.3% (95% CI, 0.1% to 0.5%).
Conclusion
Using information available to clinicians soon after completion of childhood cancer therapy, individual risk for subsequent heart failure can be predicted with reasonable accuracy and discrimination. These validated models provide a framework on which to base future screening strategies and interventions.
doi:10.1200/JCO.2014.56.1373
PMCID: PMC4314592  PMID: 25287823
Stem Cell Reports  2016;6(2):213-227.
Summary
Vα24 invariant natural killer T (iNKT) cells are a subset of T lymphocytes implicated in the regulation of broad immune responses. They recognize lipid antigens presented by CD1d on antigen-presenting cells and induce both innate and adaptive immune responses, which enhance effective immunity against cancer. Conversely, reduced iNKT cell numbers and function have been observed in many patients with cancer. To recover these numbers, we reprogrammed human iNKT cells to pluripotency and then re-differentiated them into regenerated iNKT cells in vitro through an IL-7/IL-15-based optimized cytokine combination. The re-differentiated iNKT cells showed proliferation and IFN-γ production in response to α-galactosylceramide, induced dendritic cell maturation and downstream activation of both cytotoxic T lymphocytes and NK cells, and exhibited NKG2D- and DNAM-1-mediated NK cell-like cytotoxicity against cancer cell lines. The immunological features of re-differentiated iNKT cells and their unlimited availability from induced pluripotent stem cells offer a potentially effective immunotherapy against cancer.
Graphical Abstract
Highlights
•Human iNKT cell-derived iPSCs have differentiated into Vα24 iNKT-like cells in vitro•Re-differentiated iNKT-like (Re-iNKT) cells have functionally recovered properties•Re-iNKT cells function as an adjuvant to activate antigen-specific CTLs and NK cells•Re-iNKT cells exert cytotoxic activity via NKG2D- and DNAM-1-dependent mechanism
Kaneko, Uemura, and colleagues examined functional Vα24+ human iNKT cells induced from iPS cells in vitro. The re-differentiated iNKT cells demonstrated immune-adjuvant properties to induce cancer antigen-specific cytotoxic T cells via dendritic cell stimulation and direct cytotoxicity to cancer cells by induced NKG2D expression and increased DNAM-1 activity. These features indicate that re-differentiated iNKT cells are a potential source for new immunotherapies against cancer.
doi:10.1016/j.stemcr.2016.01.005
PMCID: PMC4750166  PMID: 26862702
Journal of Clinical Oncology  2014;32(32):3643-3650.
Purpose
Survivors of Hodgkin lymphoma (HL) are at increased risk of treatment-related cardiovascular (CV) events; whether exercise modifies this risk is unknown.
Methods
Survivors of HL (n = 1,187; median age, 31.2 years) completed a questionnaire evaluating vigorous-intensity exercise behavior. CV events were collected in follow-up questionnaires and graded according to Common Terminology Criteria for Adverse Events (version 4.03). The primary end point was incidence of any major (grade 3 to 5) CV event. Poisson regression analyses were used to estimate the association between exercise exposure (metabolic equivalent [MET] hours/week−1) and risk of major CV events after adjustment for clinical covariates and cancer treatment.
Results
Median follow-up was 11.9 years (range, 1.7 to 14.3 years). Cumulative incidence of any CV event was 12.2% at 10 years for survivors reporting 0 MET hours/week−1 compared with 5.2% for those reporting ≥ 9 MET hours/week−1. In multivariable analyses, the incidence of any CV event decreased across increasing MET categories (Ptrend = .002). Compared with survivors reporting 0 MET hours/week−1, the adjusted rate ratio for any CV event was 0.87 (95% CI, 0.56 to 1.34) for 3 to 6 MET hours/week−1, 0.45 (95% CI, 0.26 to 0.80) for 9 to 12 MET hours/week−1, and 0.47 (95% CI, 0.23 to 0.95) for 15 to 21 MET hours/week−1. Adherence to national vigorous intensity exercise guidelines (ie, ≥ 9 MET hours/week−1) was associated with a 51% reduction in the risk of any CV event in comparison with not meeting the guidelines (P = .002).
Conclusion
Vigorous exercise was associated with a lower risk of CV events in a dose-dependent manner independent of CV risk profile and treatment in survivors of HL.
doi:10.1200/JCO.2014.56.7511
PMCID: PMC4220043  PMID: 25311213
Pediatric blood & cancer  2011;57(7):1210-1216.
Background
Treatment cures over 90% of children with Wilms tumor (WT) who subsequently risk late morbidity and mortality. This study describes the 25-year outcomes of 5-year Wilms tumor survivors in the Childhood Cancer Survivor Study (CCSS).
Procedure
The CCSS, a multi-institutional retrospective cohort study, assessed Wilms tumor survivors (n=1256), diagnosed 1970 – 1986, for chronic health conditions, health status, health care utilization, socioeconomic status, subsequent malignant neoplasms (SMNs), and mortality compared to the US population and a sibling cohort (n=4023).
Results
The cumulative incidence of all and severe chronic health conditions was 65.4% and 24.2% at 25 years. Hazard Ratios [HR] were 2.0, 95% Confidence Interval [CI], 1.8-2.3 for grades 1 -4 and 4.7, 95% CI, 3.6-6.1 for grade 3-4, compared to sibling group. WT survivors reported more adverse general health status than the sibling group (Prevalence Ratio [PR] 1.7; 95% CI, 1.2–2.4), but mental health status, socioeconomic outcome, and health care utilization were similar. The cumulative incidence of SMN was 3.0% (95%CI, 1.9–4.0%) and of mortality was 6.1% (95%CI, 4.7-7.4%). Radiation exposure increased the likelihood of congestive heart failure (CHF) (no doxorubicin - HR 6.6; 95%CI, 1.6-28.3; doxorubicin ≤ 250 mg/m2 - HR 13.0; 95%CI, 1.9-89.7; doxorubicin > 250 mg/m2 - HR 18.3; 95%CI, 3.8-88.2), SMN (Standardized Incidence Ratio [SIR] 9.0; 95%CI, 3.9-17.7 with and 4.9; 95%CI, 1.8-10.6 without doxorubicin) and death.
Conclusion
Long-term survivors of WT treated from 1970 to 1986 are at increased risk of treatment related morbidity and mortality 25 years from diagnosis.
doi:10.1002/pbc.23090
PMCID: PMC4634648  PMID: 21384541
Wilms Tumor; late effects; survivorship
Gut Microbes  2014;5(5):606-617.
The role of environmental reservoirs in H. pylori transmission remains uncertain due to technical difficulties in detecting living organisms in sources outside the stomach. Residents of some Canadian Arctic communities worry that contamination of the natural environment is responsible for the high prevalence of H. pylori infection in the region. This analysis aims to estimate associations between exposure to potential environmental sources of biological contamination and prevalence of H. pylori infection in Arctic Canada.
Using data from 3 community-driven H. pylori projects in the Northwest and Yukon Territories, we estimated effects of environmental exposures on H. pylori prevalence, using odds ratios (OR) and 95% confidence intervals (CI) from multilevel logistic regression models to adjust for household and community effects. Investigated exposures include: untreated drinking water; livestock; dogs; cats; mice or mouse droppings in the home; cleaning fish or game.
Our analysis did not identify environmental exposures associated clearly with increased H. pylori prevalence, except any exposure to mice or mouse droppings (OR = 4.6, CI = 1.2–18), reported by 11% of participants. Our multilevel models showed H. pylori clustering within households, but environmental exposures accounted for little of this clustering; instead, much of it was accounted for by household composition (especially: having infected household members; number of children).
Like the scientific literature on this topic, our results do not clearly implicate or rule out environmental reservoirs of H. pylori; thus, the topic remains a priority for future research. Meanwhile, H. pylori prevention research should seek strategies for reducing direct transmission from person to person.
doi:10.4161/19490976.2014.969639
PMCID: PMC4615287  PMID: 25483330
Arctic; Canada; environmental exposures; epidemiology; Helicobacter pylori;  transmission
Journal of community health  2014;39(5):857-862.
Cervical cancer incidence rates vary substantially among racial/ethnic groups in the United States (US) with women of Southeast Asian descent having the highest rates. Up to 70% of cervical cancers could be prevented by widespread use of the human papillomavirus (HPV) vaccine. However, there is a lack of information about HPV vaccine uptake among Southeast Asian girls in the US. We conducted a telephone survey of Cambodian women with daughters who were age-eligible for HPV vaccination. Survey items addressed HPV vaccination barriers, facilitators, and uptake. Our study group included 86 Cambodian mothers who lived in the Seattle metropolitan area. The proportions of survey participants who reported their daughter had initiated and completed the HPV vaccine series were only 29% and 14%, respectively. Higher levels of vaccine uptake were significantly associated with mothers having heard about the HPV vaccine from a health professional and having received a recent Pap test. Commonly cited barriers to HPV vaccination included lack of knowledge about the HPV vaccine, not having received a physician recommendation for HPV vaccination, and thinking the HPV vaccine is unnecessary in the absence of health problems. Linguistically and culturally appropriate HPV educational programs should be developed and implemented in Cambodian American communities. These programs should aim to enhance understanding of disease prevention measures, increase knowledge about the HPV vaccine, and empower women to ask their daughters’ doctors for HPV vaccination.
doi:10.1007/s10900-014-9844-8
PMCID: PMC4134757  PMID: 24532309
Cambodian American; HPV; Vaccination
PLoS ONE  2015;10(9):e0138060.
Background & Aims
The presence of resistance-associated variants (RAVs) of hepatitis C virus (HCV) attenuates the efficacy of direct acting antivirals (DAAs). The objective of this study was to characterize the susceptibility of RAVs to interferon-based therapy.
Methods
Direct and deep sequencing were performed to detect Y93H RAV in the NS5A region. Twenty nine genotype 1b patients with detectable RAV at baseline were treated by a combination of simeprevir, pegylated interferon and ribavirin. The longitudinal changes in the proportion of Y93H RAV during therapy and at breakthrough or relapse were determined.
Results
By direct sequencing, Y93H RAV became undetectable or decreased in proportion at an early time point during therapy (within 7 days) in 57% of patients with both the Y93H variant and wild type virus at baseline when HCV RNA was still detectable. By deep sequencing, the proportion of Y93H RAV against Y93 wild type was 52.7% (5.8%– 97.4%) at baseline which significantly decreased to 29.7% (0.16%- 98.3%) within 7 days of initiation of treatment (p = 0.023). The proportion of Y93H RAV was reduced in 21 of 29 cases (72.4%) and a marked reduction of more than 10% was observed in 14 cases (48.7%). HCV RNA reduction was significantly greater for Y93H RAV (-3.65±1.3 logIU/mL/day) than the Y93 wild type (-3.35±1.0 logIU/mL/day) (p<0.001).
Conclusion
Y93H RAV is more susceptible to interferon-based therapy than the Y93 wild type.
doi:10.1371/journal.pone.0138060
PMCID: PMC4569333  PMID: 26368554
PLoS ONE  2015;10(9):e0137351.
The assessment of individual risk of fibrosis progression in patients with chronic hepatitis C is an unmet clinical need. Recent genome-wide association studies have highlighted several genetic alterations as predictive risk factors of rapid fibrosis progression in chronic hepatitis C. However, most of these results require verification, and whether the combined use of these genetic predictors can assess the risk of fibrosis progression remains unclear. Therefore, genetic risk factors associated with fibrosis progression were analyzed in 176 chronic hepatitis C patients who did not achieve sustained virological response by interferon-based therapy and linked to the fibrosis progression rate (FPR). FPR was determined in all patients by paired liver biopsy performed before and after therapy (mean interval: 6.2 years). Mean FPR in patients with IL28B (rs8099917) TG/GG and PNPLA3 (rs738409) CG/GG were significantly higher than in those with IL28B TT (FPR: 0.144 vs. 0.034, P < 0.001) and PNPLA3 CC (FPR: 0.10 vs. 0.018, P = 0.005), respectively. IL28B TG/GG [hazard ratio (HR): 3.9, P = 0.001] and PNPLA3 CG/GG (HR: 3.1, P = 0.04) remained independent predictors of rapid fibrosis progression upon multivariate analysis together with average alanine aminotransferase after interferon therapy ≥40 IU/l (HR: 4.2, P = 0.002). Based on these data, we developed a new clinical score predicting the risk of fibrosis progression (FPR-score). The FPR-score identified subgroups of patients with a low (FPR: 0.005), intermediate (FPR: 0.103, P < 0.001), and high (FPR: 0.197, P < 0.001) risk of fibrosis progression. In conclusion, IL28B and PNPLA3 genotypes are associated with rapid fibrosis progression, and the FPR-score identifies patients who has a high risk of fibrosis progression and require urgent antiviral treatment.
doi:10.1371/journal.pone.0137351
PMCID: PMC4564246  PMID: 26352693
Purpose
We sought to identify factors, other than cancer-related treatment and presence/severity of chronic health conditions, which may be associated with late mortality risk among adult survivors of pediatric malignancies.
Methods
Using the Childhood Cancer Survivor Study cohort and a case-control design, 445 participants who died from causes other than cancer recurrence/progression or non-health related events were compared with 7162 surviving participants matched for primary diagnosis, age at baseline questionnaire, time from diagnosis to baseline questionnaire, and time at-risk. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for overall/cause-specific mortality. Independent measures included number/severity of chronic conditions, medical care, health-related behaviors, and health perceptions/concerns.
Results
Adjusting for education, income, chemotherapy/radiation exposures, and number/severity of chronic health conditions, an increased risk for all-cause mortality was associated with exercising fewer than 3 days/week (OR=1.72, CI:1.27 – 2.34), being underweight (OR=2.58, CI:1.55 – 4.28), increased medical-care utilization (p<0.001), and self-reported fair to poor health (p<0.001). Physical activity was associated with a higher risk of death among males (OR=3.26, CI: 1.90 – 5.61) reporting no exercise compared to those who exercised ≥3 times per week. Ever consuming alcohol was associated with a reduced risk of all-cause (OR=0.61, CI: 0.41–0.89) and other non-external causes of death (OR=0.40, CI: 0.20–0.79). Concerns/worries about future health (OR=1.54, CI: 1.10–2.71) were associated with increased all-cause mortality.
Conclusions
Factors independent of cancer treatment and chronic health conditions modify the risk of death among adult survivors of pediatric cancer.
Implications for Cancer Survivors
Continued cohort observation may inform interventions to reduce mortality.
doi:10.1007/s11764-014-0353-7
PMCID: PMC4127349  PMID: 24719269
mortality risk; childhood cancer; surveillance; cancer survivorship
Cancer  2014;120(16):2514-2521.
Purpose
Little is known about infections among adult survivors of childhood cancer. We report the occurrence of and risk factors for infections in a large cohort of survivors of childhood cancer.
Methods
Using the Childhood Cancer Survivor Study (CCSS) cohort, incidence rates of infections among 12,360 five-year survivors of childhood cancer, were compared to those of 4,023 siblings. Infection-related mortality of survivors was compared to the U.S. population. Demographic and treatment variables were analyzed using Poisson regression to determine the rate ratio (RR) and corresponding 95% confidence intervals (CI) for associations with infectious complications.
Results
Compared with the U.S. population, survivors were at an increased risk of death from infectious causes (Standardized Mortality Ratio (SMR)= 4.2; 95% CI, 3.2-5.4), with females (SMR= 3.2; 95% CI, 1.5-6.9) and those exposed to total body irradiation (SMR= 7.8; 95% CI, 1.8-33.0) having the greatest risk. Survivors also reported higher rates than siblings of overall infectious complications (RR=1.3; 95% CI, 1.2-1.4), and higher rates of all categories of infection.
Conclusion
Survivors of childhood cancer remain at elevated risk for developing infectious-related complications, with a higher risk of infection-related mortality years following therapy. Further investigation is needed to provide insight into the mechanisms for the observed excess risks.
doi:10.1002/cncr.28763
PMCID: PMC4159255  PMID: 24824782
Childhood cancer; adolescent cancer; late effects; infections; survivorship
American Journal of Epidemiology  2014;180(4):424-435.
We determined measurement properties of the Sedentary Time and Activity Reporting Questionnaire (STAR-Q), which was designed to estimate past-month activity energy expenditure (AEE). STAR-Q validity and reliability were assessed in 102 adults in Alberta, Canada (2009–2011), who completed 14-day doubly labeled water (DLW) protocols, 7-day activity diaries on day 15, and the STAR-Q on day 14 and again at 3 and 6 months. Three-month reliability was substantial for total energy expenditure (TEE) and AEE (intraclass correlation coefficients of 0.84 and 0.73, respectively), while 6-month reliability was moderate. STAR-Q-derived TEE and AEE were moderately correlated with DLW estimates (Spearman's ρs of 0.53 and 0.40, respectively; P < 0.001), and on average, the STAR-Q overestimated TEE and AEE (median differences were 367 kcal/day and 293 kcal/day, respectively). Body mass index-, age-, sex-, and season-adjusted concordance correlation coefficients (CCCs) were 0.24 (95% confidence interval (CI): 0.07, 0.36) and 0.21 (95% CI: 0.11, 0.32) for STAR-Q-derived versus DLW-derived TEE and AEE, respectively. Agreement between the diaries and STAR-Q (metabolic equivalent-hours/day) was strongest for occupational sedentary time (adjusted CCC = 0.76, 95% CI: 0.64, 0.85) and overall strenuous activity (adjusted CCC = 0.64, 95% CI: 0.49, 0.76). The STAR-Q demonstrated substantial validity for estimating occupational sedentary time and strenuous activity and fair validity for ranking individuals by AEE.
doi:10.1093/aje/kwu150
PMCID: PMC4128771  PMID: 25038920
motor activity; physical activity; reproducibility of results; sedentary lifestyle; questionnaires; validation studies

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