Patients on Antithrombotic Agents with Small Bowel Bleeding -Yield of Small Bowel Capsule Endoscopy and Subsequent Management.

BACKGROUND AND AIMS: Small bowel gastrointestinal bleeding (GIB) is associated with multiple blood transfusions, prolonged and/or multiple hospital admissions, utilization of significant healthcare resources, and negative effects on patient quality of life. There is a well-recognized association between antithrombotic medications and small bowel GIB. We aimed to identify the diagnostic yield of small bowel capsule endoscopy (SBCE) in patients on antithrombotic medications and the impact of SBCE on treatment course. METHODS: The electronic medical records of nineteen hundred eighty-six patients undergoing SBCE were retrospectively reviewed. RESULTS: The diagnostic yield for detecting stigmata of recent bleeding and/or actively bleeding lesions in SBCE was higher in patients that were on antiplatelet agents (21.6%), patients on anticoagulation (22.5%), and in patients that had their SBCE performed while they were inpatient (21.8%), when compared to the patients not on antiplatelet agents (12.1%), patients not on anticoagulation (13.5%), and with patients that had their SBCE performed in the outpatient setting (12%). Of 318 patients who had stigmata of recent bleeding and/or actively bleeding lesion(s) identified on SBCE, SBCE findings prompted endoscopic evaluation (small bowel enteroscopy, esophagogastroduodenoscopy (EGD), and/or colonoscopy) in 25.2%, with endoscopic hemostasis attempted in 52.5%. CONCLUSIONS: Our study, the largest conducted to date, emphasizes the importance of performing SBCE as part of the evaluation for suspected small bowel bleeding, particularly in patients taking antithrombotic therapy, and especially during their inpatient hospital stay.

Exposure to Non-Steady-State Oxygen Is Reflected in Changes to Arterial Blood Gas Values, Prefrontal Cortical Activity, and Systemic Cytokine Levels.

Onboard oxygen-generating systems (OBOGSs) provide increased inspired oxygen (FiO2) to mitigate the risk of neurologic injury in high altitude aviators. OBOGSs can deliver highly variable oxygen concentrations oscillating around a predetermined FiO2 set point, even when the aircraft cabin altitude is relatively stable. Steady-state exposure to 100% FiO2 evokes neurovascular vasoconstriction, diminished cerebral perfusion, and altered electroencephalographic activity. Whether non-steady-state FiO2 exposure leads to similar outcomes is unknown. This study characterized the physiologic responses to steady-state and non-steady-state FiO2 during normobaric and hypobaric environmental pressures emulating cockpit pressures within tactical aircraft. The participants received an indwelling radial arterial catheter while exposed to steady-state or non-steady-state FiO2 levels oscillating ± 15% of prescribed set points in a hypobaric chamber. Steady-state exposure to 21% FiO2 during normobaria produced arterial blood gas values within the anticipated ranges. Exposure to non-steady-state FiO2 led to PaO2 levels higher upon cessation of non-steady-state FiO2 than when measured during steady-state exposure. This pattern was consistent across all FiO2 ranges, at each barometric condition. Prefrontal cortical activation during cognitive testing was lower following exposure to non-steady-state FiO2 >50% and <100% during both normobaria and hypobaria of 494 mmHg. The serum analyte levels (IL-6, IP-10, MCP-1, MDC, IL-15, and VEGF-D) increased 48 h following the exposures. We found non-steady-state FiO2 levels >50% reduced prefrontal cortical brain activation during the cognitive challenge, consistent with an evoked pattern of neurovascular constriction and dilation.

A randomized controlled trial of the effect of supervised exercise on functional outcomes in older African American and non-Hispanic White breast cancer survivors: Are there racial differences in the effects of exercise on functional outcomes?

BACKGROUND: The objective of this study was to test the hypothesis that exercise would be more effective than a support group plus Fitbit (SG+Fitbit) program in improving functional outcomes in older breast cancer survivors (BCSs) and that race would moderate the exercise effect on outcomes. METHODS: Older African American (AA) and non-Hispanic White (NHW) BCSs were purposively recruited and enrolled into the 52-week randomized controlled trial. The interventions included 20 weeks of supervised moderate-intensity aerobic and resistance training followed by 32 weeks of unsupervised exercise called IMPROVE (n = 108) and a 20-week SG+Fitbit program followed by 32 weeks of unsupervised activity (n = 105). Study outcomes were assessed at 20 and 52 weeks. The primary outcome was the change in Short Physical Performance Battery (SPPB) scores 20 weeks from the baseline between arms. Secondary outcomes included change in the 6-Minute Walk Test (6MWT) in meters 20 weeks from the baseline between arms. General linear regression and multivariable logistic regression analyses were used. RESULTS: The mean age was 71.9 years (SD, 5.9 years), and 44% were AA. SPPB scores did not differ between arms (adjusted difference in mean change, 0.13; 95% CI, -0.28 to 0.55; P = .53). However, the exercise arm (vs the SG+Fitbit arm) improved on the 6MWT (21.6 m; 95% CI, 2.5-40.6 m; P = .03). Race moderated the exercise effect on the 6MWT (adjusted interaction effect, 43.3 m; 95% CI, 6.3-80.2 m; P = .02); this implied that the change in the adjusted mean for the 6MWT at 20 weeks from the baseline was 43.3 m higher in AA exercise participants versus NHW exercise participants. CONCLUSIONS: Combined aerobic and resistance exercise appears to improve physical performance in older BCSs, and the exercise effect might be moderated by race, with AAs appearing to derive larger benefits in comparison with NHWs. Larger studies are warranted to confirm the study findings.

Receipt of Serial Endoscopy Procedures Prior to Esophageal Adenocarcinoma Diagnosis Is Associated with Better Survival.

BACKGROUND: The poor prognosis of esophageal adenocarcinoma (EAC) has focused efforts on early detection by serial endoscopic surveillance of Barrett's esophagus (BE). Previously, we reported that receipt of endoscopy before EAC diagnosis was associated with improved survival. AIM: We aimed to refine our previous analysis, assessing surveillance as measured by performance of serial endoscopy before EAC diagnosis and evaluating its association with stage and survival. METHODS: A retrospective cohort study was performed using the Surveillance, Epidemiology and End Results-Medicare database. Patients aged ≥ 70 years with EAC diagnosed during 1998-2009 were identified. Diagnosis with BE and receipt of ≥ 2 upper endoscopic procedures within 5 years before cancer diagnosis were identified. We compared a reference group not receiving serial endoscopy to 3 patterns based on ≥ 2 endoscopy dates relative to a timepoint 2 years before cancer diagnosis: "remote," "recent," and "sustained." RESULTS: Among 5532 patients, 28% (n = 1,575) had localized stage. Thirteen percent (n = 703) received ≥ 2 endoscopic procedures before cancer diagnosis: 224, 298, and 181 in the "recent," "remote," and "sustained" groups. Serial endoscopy and prior BE were associated with localized stage ("sustained" group OR 2.95, 95% confidence interval [CI] 2.07, 4.19; prior BE OR 2.68, 95% CI 2.03, 3.56). Serial endoscopy was associated with improved survival even with adjustment for lead time bias ("sustained" group HR 0.45, 95% CI 0.37, 0.55) and length time bias. CONCLUSIONS: Sustained endoscopy was associated with earlier stage and improved survival. These results support the role of sustained surveillance in early detection of EAC.

Racial and Ethnic Cardiometabolic Risk Disparities in the Type 1 Diabetes Exchange Clinic Registry Cohort.

OBJECTIVE: To determine whether individuals from a historically underrepresented racial group have a higher cardiometabolic risk than historically represented individuals with type 1 diabetes (T1D) considering socioeconomic deprivation. METHODS: We used the multivariable logistic and linear regression models to examine socioeconomic deprivation (upper 10th percentile) by race/ethnicity interaction for each cardiometabolic risk factor and cardiometabolic risk burden score, respectively, across 6320 zip code tabulation areas. We also determined the age-adjusted prevalence of low, moderate, and high cardiometabolic risks defined as 0, 1 to 2, and 3 or more risk factors for hypertension, obesity, dyslipidemia, and off-target glycemia for non-Hispanic White (n = 15 746), non-Hispanic Black (n = 1019), Hispanic (n = 1115), and other (n = 887), respectively. RESULTS: The sample comprised 18 767 adolescents and adults with T1D. Those identifying as non-Hispanic Black were more likely to have a high cardiometabolic risk profile, including a 4.5-fold increase in the odds of off-target glycemia, a twofold increase in the odds of systolic hypertension, and 0.29 (unadjusted) and 0.46 (adjusted) increases in a higher cardiometabolic risk burden compared with non-Hispanic White individuals (P < .01). Those identifying as Hispanic had a 3.4-fold increase in the odds of off-target glycemia but were less likely to be overweight/obese or have systolic hypertension compared with non-Hispanic White. However, the lower likelihood of overweight/obesity and hypertension did not persist after considering covariates. CONCLUSION: There is a need to investigate additional determinants of racially/ethnically underrepresented cardiometabolic health, including structural racism and implicit bias in cardiometabolic care for individuals with T1D.

IMPROVE, a community-based exercise intervention versus support group to improve functional and health outcomes among older African American and Non-Hispanic White breast cancer survivors from diverse socioeconomic backgrounds: Recruitment strategies and baseline characteristics.

BACKGROUND: Behavioral intervention studies in older breast cancer survivors, particularly older African American (AA) and socioeconomic status-disadvantaged breast cancer survivors, are lacking. To inform future studies, the authors examined recruitment strategies in older breast cancer survivors who participated in an exercise intervention study. METHODS: IMPROVE is a randomized trial designed to evaluate a group-based exercise intervention versus a support group (ClinicalTrials.gov identifier, NCT02763228). Participants were aged ≥65 years who had survived stage I through III breast cancer and were within 5 years of treatment completion. Participants were recruited through multiple approaches, including peripheral, linguistic, and constituent-involving strategies that incorporated the identification of potentially eligible patients from 3 local hospitals and from State of Ohio registries and through direct clinician and community organization referrals. RESULTS: Between October 2016 and November 2019, 7487 patients were screened, 4790 were potentially eligible, and 213 were randomized into the study. The eligible:randomization rates were 4.4% overall and 84%, 8%, and 2% for recruitment using direct referrals, hospital registries, and state registries, respectively. The median age of the randomized cohort was 70 years (range, 65-88 years) and included 44% AA and 44% socioeconomic status-disadvantaged breast cancer survivors. Compared with all registry-eligible patients, directly referred-eligible patients were more likely to be AA versus Non-Hispanic White (41% vs 19%; P = .006), to be contacted successfully (100% vs 33%; P < .0001), and to accept study participation (88% vs 16%; P < .0001). CONCLUSIONS: Direct referrals appeared to be the most efficient strategy for recruiting AA survivors. Behavioral intervention studies seeking to target older AA and socioeconomic status-disadvantaged breast cancer survivors should include strategies that foster direct referrals to study participation.

Simultaneous Mapping of T1 and T2 Using Cardiac Magnetic Resonance Fingerprinting in a Cohort of Healthy Subjects at 1.5T.

BACKGROUND: Cardiac MR fingerprinting (cMRF) is a novel technique for simultaneous T1 and T2 mapping. PURPOSE: To compare T1 /T2 measurements, repeatability, and map quality between cMRF and standard mapping techniques in healthy subjects. STUDY TYPE: Prospective. POPULATION: In all, 58 subjects (ages 18-60). FIELD STRENGTH/SEQUENCE: cMRF, modified Look-Locker inversion recovery (MOLLI), and T2 -prepared balanced steady-state free precession (bSSFP) at 1.5T. ASSESSMENT: T1 /T2 values were measured in 16 myocardial segments at apical, medial, and basal slice positions. Test-retest and intrareader repeatability were assessed for the medial slice. cMRF and conventional mapping sequences were compared using ordinal and two alternative forced choice (2AFC) ratings. STATISTICAL TESTS: Paired t-tests, Bland-Altman analyses, intraclass correlation coefficient (ICC), linear regression, one-way analysis of variance (ANOVA), and binomial tests. RESULTS: Average T1 measurements were: basal 1007.4±96.5 msec (cMRF), 990.0±45.3 msec (MOLLI); medial 995.0±101.7 msec (cMRF), 995.6±59.7 msec (MOLLI); apical 1006.6±111.2 msec (cMRF); and 981.6±87.6 msec (MOLLI). Average T2 measurements were: basal 40.9±7.0 msec (cMRF), 46.1±3.5 msec (bSSFP); medial 41.0±6.4 msec (cMRF), 47.4±4.1 msec (bSSFP); apical 43.5±6.7 msec (cMRF), 48.0±4.0 msec (bSSFP). A statistically significant bias (cMRF T1 larger than MOLLI T1 ) was observed in basal (17.4 msec) and apical (25.0 msec) slices. For T2 , a statistically significant bias (cMRF lower than bSSFP) was observed for basal (-5.2 msec), medial (-6.3 msec), and apical (-4.5 msec) slices. Precision was lower for cMRF-the average of the standard deviation measured within each slice was 102 msec for cMRF vs. 61 msec for MOLLI T1 , and 6.4 msec for cMRF vs. 4.0 msec for bSSFP T2 . cMRF and conventional techniques had similar test-retest repeatability as quantified by ICC (0.87 cMRF vs. 0.84 MOLLI for T1 ; 0.85 cMRF vs. 0.85 bSSFP for T2 ). In the ordinal image quality comparison, cMRF maps scored higher than conventional sequences for both T1 (all five features) and T2 (four features). DATA CONCLUSION: This work reports on myocardial T1 /T2 measurements in healthy subjects using cMRF and standard mapping sequences. cMRF had slightly lower precision, similar test-retest and intrareader repeatability, and higher scores for map quality. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1 J. Magn. Reson. Imaging 2020;52:1044-1052.

Recruitment Strategies for Nurse Enrollment in an Online Study.

BACKGROUND: Although there is a great deal of literature regarding effective recruitment and challenges of recruiting specific patient populations, there is less known about best practices for recruitment of nurses as study subjects. OBJECTIVES: The purpose of this article is to report our experience with recruitment and retention for a randomized trial of an online educational program to prepare oncology nurses to discuss oncology clinical trials with patients. METHODS: The study population included currently employed oncology nurses with direct patient interaction. There were three phases of this study: (1) qualitative interviews, (2) a pilot test, and (3) the randomized trial. Phase 3 was rolled out in five waves of recruitment. The distinct phases of the study-and the gradual roll out of recruitment during Phase 3-allowed us to test and refine our recruitment and retention methods for the randomized trial. Upon analysis of our response rate and attrition after the first wave of recruitment in Phase 3, we made several changes to improve recruitment and retention, including adding incentives, shortening the survey, and increasing the number of reminders to complete the program. RESULTS: The response rate was higher when we used both e-mail and U.S. postal mail solicitations. After the first wave of recruitment in the final phase, changes in our strategies did not increase our overall response rate significantly; however, the rate of attrition following baseline declined. DISCUSSION: Recruitment planning is an important component of successful clinical research. The use of the Internet for both recruitment of subjects and testing of interventions remains a cost-effective and potentially high yield methodology. Our research demonstrated several successful approaches to yield increased participation and retention of subjects, including seeking formal relationships with professional organizations as sponsors or supporters, providing meaningful incentives to participants, keeping surveys or questionnaires as short as possible, and planning multiple follow-up contacts from the outset.

MR Fingerprinting and ADC Mapping for Characterization of Lesions in the Transition Zone of the Prostate Gland.

BackgroundPreliminary studies have shown that MR fingerprinting-based relaxometry combined with apparent diffusion coefficient (ADC) mapping can be used to differentiate normal peripheral zone from prostate cancer and prostatitis. The utility of relaxometry and ADC mapping for the transition zone (TZ) is unknown.PurposeTo evaluate the utility of MR fingerprinting combined with ADC mapping for characterizing TZ lesions.Materials and MethodsTZ lesions that were suspicious for cancer in men who underwent MRI with T2-weighted imaging and ADC mapping (b values, 50-1400 sec/mm2), MR fingerprinting with steady-state free precession, and targeted biopsy (60 in-gantry and 15 cognitive targeting) between September 2014 and August 2018 in a single university hospital were retrospectively analyzed. Two radiologists blinded to Prostate Imaging Reporting and Data System (PI-RADS) scores and pathologic diagnosis drew regions of interest on cancer-suspicious lesions and contralateral visually normal TZs (NTZs) on MR fingerprinting and ADC maps. Linear mixed models compared two-reader means of T1, T2, and ADC. Generalized estimating equations logistic regression analysis was used to evaluate both MR fingerprinting and ADC in differentiating NTZ, cancers and noncancers, clinically significant (Gleason score ≥ 7) cancers from clinically insignificant lesions (noncancers and Gleason 6 cancers), and characterizing PI-RADS version 2 category 3 lesions.ResultsIn 67 men (mean age, 66 years ± 8 [standard deviation]) with 75 lesions, targeted biopsy revealed 37 cancers (six PI-RADS category 3 cancers and 31 PI-RADS category 4 or 5 cancers) and 38 noncancers (31 PI-RADS category 3 lesions and seven PI-RADS category 4 or 5 lesions). The T1, T2, and ADC of NTZ (1800 msec ± 150, 65 msec ± 22, and [1.13 ± 0.19] × 10-3 mm2/sec, respectively) were higher than those in cancers (1450 msec ± 110, 36 msec ± 11, and [0.57 ± 0.13] × 10-3 mm2/sec, respectively; P < .001 for all). The T1, T2, and ADC in cancers were lower than those in noncancers (1620 msec ± 120, 47 msec ± 16, and [0.82 ± 0.13] × 10-3 mm2/sec, respectively; P = .001 for T1 and ADC and P = .03 for T2). The area under the receiver operating characteristic curve (AUC) for T1 plus ADC was 0.94 for separation. T1 and ADC in clinically significant cancers (1440 msec ± 140 and [0.58 ± 0.14] × 10-3 mm2/sec, respectively) were lower than those in clinically insignificant lesions (1580 msec ± 120 and [0.75 ± 0.17] × 10-3 mm2/sec, respectively; P = .001 for all). The AUC for T1 plus ADC was 0.81 for separation. Within PI-RADS category 3 lesions, T1 and ADC of cancers (1430 msec ± 220 and [0.60 ± 0.17] × 10-3 mm2/sec, respectively) were lower than those of noncancers (1630 msec ± 120 and [0.81 ± 0.13] × 10-3 mm2/sec, respectively; P = .006 for T1 and P = .004 for ADC). The AUC for T1 was 0.79 for differentiating category 3 lesions.ConclusionMR fingerprinting-based relaxometry combined with apparent diffusion coefficient mapping may improve transition zone lesion characterization.© RSNA, 2019Online supplemental material is available for this article.

Ser-486/491 phosphorylation and inhibition of AMPKα activity is positively associated with Gleason score, metastasis, and castration-resistance in prostate cancer: A retrospective clinical study.

BACKGROUND: We previously demonstrated that adenosine monophosphate-activated protein kinase (AMPKα) activity is significantly inhibited by Ser-486/491 phosphorylation in cell culture and in vivo models of metastatic and castration-resistant prostate cancer, and hypothesized these findings may translate to clinical specimens. METHODS: In this retrospective, single-institution pilot study, 45 metastatic prostate cancer cases were identified within the University Hospitals Cleveland Medical Center Pathology Archive with both metastasis and matched primary prostate tumor specimens in formalin-fixed, paraffin-embedded blocks, and complete electronic medical records. Thirty non-metastatic, hormone-dependent prostate cancer controls, who were progression-free as defined by undetectable prostate specific antigen for at least 79.6 months (range 79.6-136.0 months), and matched metastatic cases based on age, race, and year of diagnosis. All specimens were collected from 1991 to 2014; primary tumor specimens were obtained via diagnostic biopsy or prostatectomy, and metastasis specimens obtained via surgery or perimortem. 5-µ sequential slides were processed for phospho-Ser-486/491 AMPKα1 /α2 , phospho-Thr-172 AMPKα, AMPKα1 /α2 , phospho-Ser-792 Raptor, phospho-Ser-79 acetyl-CoA carboxylase, and phospho-Ser-872, 3-hydroxy-3-methylglutaryl-CoA reductase immunohistochemistry to determine expression, phosphorylation pattern, and activity of AMPKα. RESULTS: Increased inhibitory Ser-486/491 AMPKα1 /α2 phosphorylation, increased AMPKα protein expression, decreased AMPKα activity, and loss of nuclear AMPKα and p-AMPKα are associated with prostate cancer progression to metastasis. Increased p-Ser-486/491 AMPKα1 /α2 was also positively correlated with higher Gleason grade and progression to castration-resistance. CONCLUSIONS: p-Ser-486/491 AMPKα1 /α2 is a novel marker of prostate cancer metastasis and castration-resistance. Ser-486/491 phosphokinases should be pursued as targets for metastatic and castration-resistant prostate cancer chemotherapy.

Development of a Combined MR Fingerprinting and Diffusion Examination for Prostate Cancer.

Purpose To develop and evaluate an examination consisting of magnetic resonance (MR) fingerprinting-based T1, T2, and standard apparent diffusion coefficient (ADC) mapping for multiparametric characterization of prostate disease. Materials and Methods This institutional review board-approved, HIPAA-compliant retrospective study of prospectively collected data included 140 patients suspected of having prostate cancer. T1 and T2 mapping was performed with fast imaging with steady-state precession-based MR fingerprinting with ADC mapping. Regions of interest were drawn by two independent readers in peripheral zone lesions and normal-appearing peripheral zone (NPZ) tissue identified on clinical images. T1, T2, and ADC were recorded for each region. Histopathologic correlation was based on systematic transrectal biopsy or cognitively targeted biopsy results, if available. Generalized estimating equations logistic regression was used to assess T1, T2, and ADC in the differentiation of (a) cancer versus NPZ, (b) cancer versus prostatitis, (c) prostatitis versus NPZ, and (d) high- or intermediate-grade tumors versus low-grade tumors. Analysis was performed for all lesions and repeated in a targeted biopsy subset. Discriminating ability was evaluated by using the area under the receiver operating characteristic curve (AUC). Results In this study, 109 lesions were analyzed, including 39 with cognitively targeted sampling. T1, T2, and ADC from cancer (mean, 1628 msec ± 344, 73 msec ± 27, and 0.773 × 10-3 mm2/sec ± 0.331, respectively) were significantly lower than those from NPZ (mean, 2247 msec ± 450, 169 msec ± 61, and 1.711 × 10-3 mm2/sec ± 0.269) (P < .0001 for each) and together produced the best separation between these groups (AUC = 0.99). ADC and T2 together produced the highest AUC of 0.83 for separating high- or intermediate-grade tumors from low-grade cancers. T1, T2, and ADC in prostatitis (mean, 1707 msec ± 377, 79 msec ± 37, and 0.911 × 10-3 mm2/sec ± 0.239) were significantly lower than those in NPZ (P < .0005 for each). Interreader agreement was excellent, with an intraclass correlation coefficient greater than 0.75 for both T1 and T2 measurements. Conclusion This study describes the development of a rapid MR fingerprinting- and diffusion-based examination for quantitative characterization of prostatic tissue. © RSNA, 2017 Online supplemental material is available for this article.

Vulnerable elders survey and socioeconomic status predict functional decline and death among older women with newly diagnosed nonmetastatic breast cancer.

BACKGROUND: The purpose of this study was to determine the ability of the Vulnerable Elders Survey (VES-13) to predict the composite outcome of functional decline and death within 12 months of breast cancer treatment among women 65 years old or older with newly diagnosed stage I to III breast cancer. METHODS: Two hundred and six participants were recruited from ambulatory oncology clinics at an academic center between April 2008 and April 2013. Participants competed the VES-13 at baseline just before neoadjuvant/adjuvant treatment. The primary outcome, functional decline/death, was defined as either a decrease of at least 1 point on the Activities of Daily Living scale and/or the Instrumental Activities of Daily Living scale or death between baseline and 12 months (yes or no). RESULTS: One hundred and eighty four participants (89%) completed 12 months of follow-up. Twenty-two percent functionally declined (n = 34) or died (n = 7). Univariately, with increasing VES-13 scores, the estimated risk of functional decline/death rose from 23% for participants with a VES-13 score of 3 to 76% for participants with a VES-13 score of 10. In multivariate logistic regression analysis, VES-13 scores (adjusted odds ratio, 1.37; 95% confidence interval, 1.18-1.57) and having a high school education or less (adjusted odds ratio, 2.47; 95% confidence interval, 1.08-5.65) were independent predictors of functional decline/death (area under the receiver operator curve, 0.79). CONCLUSIONS: Among older women with newly diagnosed nonmetastatic breast cancer, approximately 1 in 5 functionally declined and/or died within 12 months of breast cancer treatment initiation. Women with high school education or less were disproportionately affected. The VES-13 is a useful instrument for the early identification of those at risk for functional decline and/or death. Cancer 2016;122:2579-86. © 2016 American Cancer Society.

Trajectory and correlates of growth of extremely-low-birth-weight adolescents.

BACKGROUND: Catch-up growth may predispose to obesity and metabolic sequelae. We sought to examine the trajectory and correlates of growth and catch up among extremely-low-birth-weight (ELBW) (<1 kg) adolescents. METHODS: A cohort study of 148 neurologically normal ELBW children and 115 normal-birth-weight (NBW) controls born during the period 1992-1995 was conducted. Longitudinal measures of gender-specific growth of ELBW children from birth, in addition to growth and measures of obesity of ELBW and NBW children at 14 y, were evaluated. RESULTS: Following neonatal growth failure, ELBW children had accelerated growth, but at 8 y, they still had lower weight and height z scores than NBW children. By 14 y, ELBW boys had caught up in growth to their NBW controls, but ELBW girls remained significantly smaller. ELBW children, however, did not differ from their controls in measures of obesity. In hierarchical multiple regression analyses, only maternal BMI and weight gain during infancy and childhood predicted the ELBW children's 14-y weight z scores, BMI z scores, and abdominal circumference. Perinatal risk factors, including intrauterine growth, only predicted growth up to 20 mo. CONCLUSION: Maternal BMI and rate of growth, rather than perinatal factors, predict 14-y obesity among neurologically normal ELBW adolescents.

Circulating Monocytes Are Predictive and Responsive in Moderate-to-Severe Plaque Psoriasis Subjects Treated with Apremilast.

Monocytes play a critical role in the inflammation associated with psoriasis, and their abnormalities have been reported as biomarkers of cardiovascular event risk, a psoriasis comorbidity. Monocytic cells in chronic inflammatory disorders express elevated levels of cAMP phosphodiesterase. Restoring cAMP levels using the oral cAMP phosphodiesterase-4 inhibitor, apremilast, improves clinical outcomes for a subset of patients with psoriasis. We asked whether aberrant monocyte subsets or transcriptomic pathways can function as biomarkers of psoriasis endotypes that can predict enhanced clinical responses to cAMP phosphodiesterase inhibition. A 16-week open-label study of 22 patients with monocyte flow cytometric and transcriptomic analysis was performed. Subjects with elevated hyperadhesive monocyte doublets at baseline were more likely to be responders to apremilast (P < .0001); 82% of subjects with elevated hyperadhesive monocyte doublets achieved 50% reduction in PASI compared with 46% in those without elevated doublets. We observed a significant reduction in hyperadhesive monocyte-containing doublets and monocyte-platelet aggregates, suggesting an effect of apremilast on the adhesiveness of blood monocytes during chronic inflammation. Monocyte differentially expressed gene transcripts predictive of clinical response uncovered pharmacoendotypes with distinct patterns of nucleotide metabolism, energetics, and differentiation. Further study to understand the basis of drug responsiveness and to develop an apremilast psoriasis treatment algorithm using monocyte-refined gene expression is required to validate and become practical in clinical use, offering patients a test that personalizes their likelihood of clinical response.

Haplo-cord transplant. Realizing the potential of umbilical cord blood grafts. - A review of techniques and analysis of outcomes.

The combination of cord blood transplant with progenitor cells from partially HLA-matched adult donors (haplo-cord transplant) has been used over the past two decades. In Europe and the US the adult donor graft is CD34 selected and provides early hematopoiesis, but durable engraftment derives from the cord blood graft (CD34 selected haplo-cord). Neutrophil recovery is prompt and rates of acute and chronic GVHD are low. Recent Chinese studies combine cord blood grafts with T-replete haplo-identical grafts (unmodified haplo-cord). The haplo graft usually establishes dominance and UCB chimerism is rarely detected. Comparison studies suggest considerably decreased rates of relapse and improved outcomes, compared with either haplo-identical transplant or CBU transplant, particularly in patients with advanced leukemia. A recent prospective randomized study confirms this. Haplo-cord mitigates the engraftment delay of UCB transplant. The unique biology of UCB grafts results in low GVHD and improved GVL especially beneficial in high-risk disease.

A multicenter study of posttransplantation low-dose inotuzumab ozogamicin to prevent relapse of acute lymphoblastic leukemia.

ABSTRACT: The curative potential of allogeneic hematopoietic transplantation (allo-HCT) in patients with acute lymphoblastic leukemia (ALL) is hampered by relapse. Inotuzumab ozogamicin (INO) is an anti-CD22 monoclonal antibody bound to calicheamicin, which has significant activity against ALL. We hypothesized that low-dose INO would be safe and feasible after allo-HCT. Therefore, we conducted a phase 1 study to determine the dose and safety in this setting. Patients were eligible if they were aged 16 to 75 years, had undergone allo-HCT for CD22+ ALL, were in complete remission (CR) after allo-HCT, had high risk of recurrence, were between day 40 and 100 after allo-HCT with adequate graft function, and did not have a history of sinusoidal obstruction syndrome (SOS). The objectives of this trial were to define INO maximum tolerated dose (MTD), to determine post-allo-HCT INO safety, and to measure 1-year progression-free survival (PFS). The trial design followed a "3+3" model. The treatment consisted of INO given on day 1 of 28-day cycles. Dose levels were 0.3 mg/m2, 0.4 mg/m2, 0.5 mg/m2, and 0.6 mg/m2. Median age was 44 years (range, 17-66 years; n = 18). Disease status at transplantation was first CR (n = 14) or second CR or beyond (n = 4). Preparative regimen was of reduced intensity in 72% of patients who received transplantation. Most common toxicity was thrombocytopenia. There were no instances of SOS; the MTD was 0.6 mg/m2. One-year nonrelapse mortality was 5.6%. With a median follow-up of 18.1 months (range, 8.6-59 months) 1-year post-allo-HCT PFS and overall survival is 89% and 94%, respectively. Low-dose INO has a favorable safety profile and was associated with high rates of 1-year PFS. This trial was registered at www.clinicaltrials.gov as #NCT03104491.

The functional duality of HoxB4 in hematopoietic reconstituting cells.

Transplantation of CD34⁺ hematopoietic reconstituting cells (HRC) is an important treatment modality. The cells needed for clinical hematopoietic reconstitution after myeloablation most commonly derive from bone marrow which have been mobilized into the peripheral blood. The number of CD34⁺ cells in mobilized blood samples is used to indicate the appropriateness of transplantation although it does not evaluate the two necessary functions for successful transplantation: long-term reconstitution mediated by cells with self-renewing proliferation and short-term hematopoietic differentiation mediated by progenitor cells. Using a novel high-resolution immunophenotyping technology on a flow cytometric platform, we have assessed uniformly mobilized CD34⁺ cells for expression levels of 16 molecules previously associated with HRC function and sought correlations of these expression data with functional short-term assays for colony formation that do predict successful transplantation. We found that colony-forming units were significantly correlated with HoxB4 expression, which was explained by the number of CD34⁺ cells in the samples. However, analysis of colony-forming units normalized to the CD34⁺ cell count revealed a significant negative correlation with HoxB4 expression. Thus, increased levels of HoxB4 enhance CD34⁺ cell number via self-renewing expansion but concomitantly depreciate the capacity for short-term differentiation per cell. Our findings demonstrate the translation of experimental findings into a clinical setting and suggest that the expression level of HoxB4 in CD34⁺ cells can be used as a measure of a sample's appropriateness for transplantation.

Examining how congruence in and satisfaction with dyadic care type appraisal contribute to quality of life in heart failure care dyads.

AIMS: Given the complexity of heart failure (HF) management, persons with HF and their informal caregivers often engage in dyadic illness management. It is unknown how congruent appraisal of dyadic HF care type is associated with dyadic health. Our aim was to examine how congruence in and satisfaction with appraisal of dyadic HF care type contribute to quality of life (QOL) for dyads. METHODS AND RESULTS: This is a secondary analysis of cross-sectional data on 275 HF care dyads (patients 45.1% female, caregivers 70.5% female). Congruent appraisal and satisfaction were assessed using the Dyadic Symptom Management Type instrument. Quality of life was measured using the Short Form-12. Multilevel dyadic models were estimated to examine the contribution of congruence and satisfaction with dyadic care type to physical and mental QOL. Congruent appraisal of dyadic care type was positively associated with caregivers' mental QOL (B = 2.69, P = 0.026). Satisfaction with dyadic care type was positively associated with physical and mental QOL for persons with HF (B = 1.58, P = 0.011 and B = 2.09, P = 0.002, respectively) and informal caregivers (B = 1.70, P = 0.004 and B = 2.90, P < 0.001, respectively), while controlling for age, New York Heart Association class, daily hours spent together, relationship type, and congruence with dyadic care type. CONCLUSION: Satisfaction with dyadic care type appraisal was a stronger contributor to QOL for HF care dyads, compared with congruent appraisals. It is important to understand reasons for dissatisfaction within the dyad to assist dyad members in reaching shared appraisals while managing HF.

Sleep health dimensions are associated with next-day symptoms in young adults with type 1 diabetes.

OBJECTIVE: We investigated intra-individual reciprocal associations between sleep health dimensions (individual and composite) and symptoms among young adults with type 1 diabetes (T1D). DESIGN AND MEASUREMENTS: Cross-lagged multilevel models were used to analyze electronic diary-reported sleep and symptom patterns over 7 days at waketime in 42 young adults with T1D. Sleep health dimensions included regularity, satisfaction, alertness, timing, efficiency (percentage of time spent asleep), and duration (total sleep time) and symptoms included mood, fatigue, and pain. Covariates included biological sex and age. SETTING AND PARTICIPANTS: We recruited young adults (mean age 21.5 ± 2.1 years, HbA1c 6.8%, 85% female, 10% gender minority) with T1D for at least 6 months and no other major medical or psychiatric comorbidity from social media platforms, the College Diabetes Network, and ResearchMatch. RESULTS: On days with a better sleep health composite, participants reported lower next-day symptoms (higher mood, lower fatigue, and lower pain) and on days when participants reported lower symptoms, participants reported better sleep health (as a composite). Several individual sleep health dimensions led to lower next-day symptoms (eg, higher satisfaction, alertness, and efficiency and higher mood); however, symptoms were no longer predictive of next-day sleep when controlling for prior day sleep. CONCLUSIONS: Optimal sleep health is an antecedent of fewer next day symptoms. Sleep health dimensions likely have positive additive effects on lower symptoms as some of the individual sleep health dimensions were not significantly associated with some symptoms among young adults with T1D.

The Impact of Prophylactic Cranial Irradiation and Consolidative Thoracic Radiation Therapy for Extensive Stage Small-Cell Lung Cancer in the Transition to the Chemo-Immunotherapy Era: A Single Institution Series.

INTRODUCTION: Extensive-stage small-cell lung cancer (ES-SCLC) continues to have poor survival due to its aggressive behavior, despite improvements with incorporation of immunotherapy with standard chemotherapy. Controversy exists regarding the role of consolidative thoracic radiation therapy (TRT) and prophylactic cranial irradiation (PCI) in ES-SCLC due to high recurrence rates. We report our institutional result of the benefit of PCI and TRT in ES-SCLC. METHODS: Patients with ES-SCLC without intracranial metastasis at diagnosis (N = 163) were included. All patients completed systemic therapy with or without immunotherapy based on time of standard of care. Cohorts were divided by systemic therapy use and further subdivided by treatment with PCI and TRT. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method with log-rank test for comparison. The effects of TRT and PCI were estimated by multivariable (MVA) Cox regression. RESULTS: Seventy-four patients (45.4%) received TRT, and 33.1% (n = 54) received PCI. The median follow-up was 11 months (3-85 months). PCI improved median OS to 15 months from 10 months, P = .02) and median PFS to 8.5 months from 5 months (P = .02) which remained significant on MVA, P = .02 and P = .02, respectively. TRT improved OS on UVA (P = 0.002) but was not significant on MVA. TRT did not improve PFS. CONCLUSION: This study including chemotherapy and chemo-immunotherapy suggests improved outcomes with addition of PCI in patients with ES-SCLC while TRT did not show benefit to either OS or PFS. A future trial is needed to evaluate the role of TRT and PCI in the era of chemo-immunotherapy.