First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma.

Alternatively spliced tissue factor (asTF) promotes the progression of pancreatic ductal adenocarcinoma (PDAC) by activating ß1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class humanized inhibitory anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Following in vivo screening of three asTF-proficient human PDAC cell lines, we chose to make use of KRAS G12V-mutant human PDAC cell line PaCa-44, which yields aggressive primary orthotopic tumors with spontaneous spread to PDAC-relevant anatomical sites, along with concomitant severe leukocytosis. The experimental design featured orthotopic tumors formed by luciferase labeled PaCa-44 cells; administration of hRabMab1 alone or in combination with gemcitabine/paclitaxel (gem/PTX); and the assessment of the treatment outcomes on the primary tumor tissue as well as systemic spread. When administered alone, hRabMab1 exhibited poor penetration of tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem/PTX, which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem/PTX significantly reduced metastatic spread. RNA-seq analysis of primary tumors showed that the addition of hRabMab1 to gem/PTX enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem/PTX eliminated tumor cell-induced leukocytosis. We here demonstrate for the first time that hRabMab1 may help suppress metastasis in PDAC. hRabMab1's ability to improve the efficacy of chemotherapy is significant and warrants further investigation.

Acoustics and aerodynamic effects following glottal and infraglottal medialization in an excised larynx model.

OBJECTIVE: This study aimed to investigate the impact of the implant's vertical location during Type 1 Thyroplasty (T1T) on acoustics and glottal aerodynamics using excised canine larynx model, providing insights into the optimal technique for treating unilateral vocal fold paralysis (UVFP). METHODS: Measurements were conducted in six excised canine larynges using Silastic implants. Two implant locations, glottal and infraglottal, were tested for each larynx at low and high subglottal pressure levels. Acoustic and intraglottal flow velocity field measurements were taken to assess vocal efficiency (VE), cepstral peak prominence (CPP), and the development of intraglottal vortices. RESULTS: The results indicated that the implant's vertical location significantly influenced vocal efficiency (p = 0.045), with the infraglottal implant generally yielding higher VE values. The effect on CPP was not statistically significant (p = 0.234). Intraglottal velocity field measurements demonstrated larger glottal divergence angles and stronger vortices with the infraglottal implant. CONCLUSION: The findings suggest that medializing the paralyzed fold at the infraglottal level rather than the glottal level can lead to improved vocal efficiency. The observed larger divergence angles and stronger intraglottal vortices with infraglottal medialization may enhance voice outcomes in UVFP patients. These findings have important implications for optimizing T1T procedures and improving voice quality in individuals with UVFP. Further research is warranted to validate these results in clinical settings.

Bone mineral density in young adults 5 to 11 years after adolescent metabolic and bariatric surgery for severe obesity compared to peers.

OBJECTIVE: Metabolic and bariatric surgery (MBS) is associated with decreased bone mineral density (BMD) in adults. The long-term impact of MBS during adolescence on BMD is unknown. We report bone health status 5 to 11 years after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) from the Teen-LABS study cohort. METHODS: Between 2016 and 2022, BMD was measured by dual energy x-ray absorptiometry (DXA) in 106 young adults who had undergone MBS as adolescents. Volumetric BMD by peripheral quantitative computed tomography was measured on a subset. Ninety-one controls who had not undergone MBS were recruited for comparison. RESULTS: In cases (RYGB: mean age 26.8 ± 1.9 years, mean BMI 42.1 ± 9.9 kg/m2, VSG: mean age 25.1 ± 2.1 years, mean BMI 37.1 ± 8.4 kg/m2), compared to controls (mean age 26.5 ± 2.7 years, mean BMI 40.2 ± 8.7 kg/m2) (age p < 0.001, BMI p = 0.02), adjusted mean DXA-BMD (g/cm2) of the RYGB (n = 58) and VSG (n = 48) groups were lower at the hip (-10.0% and -6.3%), femoral neck (-9.6% and -5.7%) and ultra-distal radius (-7.9% and -7.0%; all p < 0.001), respectively. DXA-BMD did not differ between RYGB and VSG groups. Trabecular volumetric BMD at the radius and tibia were lower in the RYGB (-30% and -26%) and VSG (-15% and -14%) groups compared to the control group (p < 0.001). Greater time since MBS was associated with lower BMD Z-scores at the hip (p = 0.05) and femoral neck (p = 0.045). Percent change in body mass index (BMI) from baseline or in the first year after MBS were not associated with bone measures at a median of 9.3 years post MBS. CONCLUSION: BMD, especially of the hip and femoral neck, was lower in young adults who underwent MBS during adolescence compared to matched peers who had not undergone MBS. BMD Z-scores of the femoral neck were inversely associated with time since MBS but were not associated with BMI change.

Bone mineral density 5 to 11 years after metabolic and bariatric surgery in adolescents with severe obesity compared to peers.

Objective: Metabolic and bariatric surgery (MBS) is associated with decreased bone mineral density (BMD) in adults. The long-term impact of MBS during adolescence on BMD is unknown. We report bone health status 5 to 11 years after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) from the Teen-LABS study cohort. Methods: Between 2016 and 2022, BMD was measured by dual energy x-ray absorptiometry (DXA) in 106 young adults who had undergone MBS as adolescents. Volumetric BMD by peripheral quantitative computed tomography was measured on a subset. Ninety-one controls who had not undergone MBS were recruited for comparison. Results: Compared to controls, adjusted mean DXA-BMD of the RYGB (n = 58) and VSG (n = 48) groups were lower at the hip (-10.0% and - 6.3%), femoral neck (-9.6% and - 5.7%) and ultra-distal radius (-7.9% and - 7.0%; all p < 0.001), respectively. DXA-BMD did not differ between RYGB and VSG groups. Trabecular volumetric BMD at the radius and tibia were lower in the RYGB (-30% and - 26%) and VSG (-15% and - 14%) groups compared to the control group (p < 0.001). Greater time since MBS was associated with lower BMD Z-scores at the hip (p = 0.05) and femoral neck (p = 0.045). Percent change in body mass index (BMI) from baseline or in the first year after MSB were not associated with bone measures at a median of 9.3 years post MSB. Conclusion: BMD, especially of the hip and femoral neck, was lower in young adults who underwent MBS during adolescence compared to matched peers who had not undergone MBS. BMD Z-scores of the femoral neck decreased with time since MBS but were not associated with BMI change.

Meta-analysis of Osteopontin splice variants in cancer.

BACKGROUND: The cytokine Osteopontin is a mediator of tumor progression and cancer metastasis. In 2006, we reported that (in addition to the full-length form -a) splice variants of Osteopontin (forms -b and -c) are produced selectively by transformed cells. Through June 2021, 36 PubMed-indexed journal articles have studied Osteopontin splice variants in various cancer patients. METHODS: Applying a categorical approach previously developed by us, here we conduct a meta-analysis of the pertinent literature. We supplement this with evaluation of the relevant entries in the TSVdb database, which focusses on splice variant expression, thus including the additional variants -4 and -5. The analysis covers 5886 patients across 15 tumors from the literature and 10,446 patients across 33 tumors from TSVdb. RESULTS: The database yields positive results more frequently than the categorical meta-analysis. The two sources are in agreement on the elevation of OPN-a, OPN-b, and OPN-c in lung cancer and the elevation of OPN-c in breast cancer as compared to healthy tissue. Specific splice variants are associated with grade, stage, or patient survival pertaining to various cancers. CONCLUSIONS: There are cases of persisting discrepancies, which require further investigation to clarify the Osteopontin splice variant utilization, so that their diagnostic, prognostic and potentially predictive potential can be brought to fruition.

Effect of surgical versus medical therapy on estimated cardiovascular event risk among adolescents with type 2 diabetes and severe obesity.

BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of mortality in type 2 diabetes (T2D). Better interventions are needed to mitigate the high lifetime risk for CVD in youth T2D. OBJECTIVE: To compare 30-year risk for CVD events in 2 cohorts of adolescents with T2D and severe obesity undergoing medical or surgical treatment of T2D. SETTING: Longitudinal multicenter studies at University hospitals. METHODS: A secondary analysis of data collected from the participants with T2D enrolled in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n = 30) and participants of similar age and racial distribution from the Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY, n = 63) studies was performed. Teen-LABS participants underwent metabolic bariatric surgery (MBS). TODAY participants were randomized to metformin alone or in combination with rosiglitazone or intensive lifestyle intervention, with insulin therapy given for glycemic progression. A 30-year CVD event score developed by the Framingham Heart Study was the primary outcome, assessed at baseline (preoperatively for Teen-LABS), 1 year, and 5 years of follow-up. RESULTS: Participants with T2D from Teen-LABS (n = 30; mean ± SD age = 16.9 ± 1.3 yr; 70% female; 60% white; body mass index (BMI) = 54.4 ± 9.5 kg/m2) and TODAY (n = 63; 15.3 ± 1.3 yr; 56% female; 71% white; BMI 40.5 ± 4.9 kg/m2) were compared. The likelihood of CVD events was higher in Teen-LABS versus TODAY at baseline (17.66 [1.59] versus 12.11 [.79]%, adjusted P = .002). One year after MBS, event risk was significantly lower in Teen-LABS versus TODAY (6.79 [1.33] versus 13.64 [0.96]%, adjusted P < .0001), and sustained at 5 years follow-up (adjusted P < .0001). CONCLUSION: Despite higher pretreatment risk for CVD events, treatment with MBS resulted in a reduction in estimated CVD event risks, whereas medical therapy associated with an increase in risk among adolescents with T2D and severe obesity.

Maternal cadmium exposure and neurobehavior in children: The HOME study.

BACKGROUND: It is unclear whether cadmium (Cd) exposure during fetal brain development is associated with child neurobehavior. OBJECTIVE: To examine the potential associations between Cd exposure during pregnancy and neurobehavior among children. METHODS: We used data from 276 children in the Health Outcomes and Measures of the Environment (HOME) Study, a well-established prospective pregnancy and birth cohort. We measured maternal urinary Cd concentrations at 26 weeks of gestation. For cognitive function, we assessed Mental Development Index (MDI) and Full-Scale Intelligence Quotient (FSIQ) using the Bayley Scales of Infant Development-II, the Wechsler Preschool and Primary Scales of Intelligence-III, or the Wechsler Intelligence Scales for Children-IV at ages 1, 2, 3, 5, and 8 years. We assessed child behaviors using the Behavior Assessment System for Children-2 at ages 2, 3, 4, 5, and 8 years, yielding four composite measures: Externalizing Problems, Internalizing Problems, Behavioral Symptoms Index, and Adaptive Skills. We used linear mixed models with covariate adjustment to estimate the associations between maternal urinary Cd concentrations and child neurobehavior. RESULTS: We categorized study participants into three groups based on maternal urinary Cd concentrations (Group 1: < limit of detection (LOD), Group 2: 0.06-0.22 µg/g creatinine, Group 3: ＞0.22 µg/g creatinine). In linear mixed models adjusting for maternal and child characteristics, maternal urinary Cd levels were not significantly associated with cognitive function at ages 1, 2, 3, 5, and 8 years or with behavioral composite measures at 2, 3, 4, 5, and 8 years. CONCLUSIONS: No significant associations were observed between maternal urinary Cd and cognitive or behavioral measures in children at 1-8 years of age in this study.

Excess skin problems among adolescents after bariatric surgery.

BACKGROUND: Bariatric surgery results in significant and durable weight loss and improved health in severely obese adolescents. An important adverse consequence of the massive weight loss after bariatric surgery is excess skin and soft tissue. The prevalence and clinical characteristics of excess skin-related symptoms have been described in adults undergoing bariatric surgery but not in adolescents. Although the higher skin elasticity of adolescents may result in fewer excess skin problems compared with adults, this hypothesis remains untested. OBJECTIVES: The purpose of the present study was to describe the natural history of excess skin and its associated complications among severely obese adolescents undergoing bariatric surgery. SETTING: University Hospitals, United States. METHODS: We evaluated data from the Teen-Longitudinal Assessment of Bariatric Surgery cohort, a prospective, multiinstitutional study of adolescents (13-19 yr) undergoing bariatric surgery. Abdominal pannus severity (graded 0-5) and excess skin symptoms were evaluated preoperatively and for the first 5 years after bariatric surgery. RESULTS: Among the 217 study participants, 198 (90%) had an abdominal pannus and 16 (7%) reported pannus-related symptoms at the time of bariatric surgery. Preoperative symptoms included intertriginous infections (n = 12, 75%), recurrent cellulitis (n = 5, 31%), and superficial cutaneous ulcerations (n = 1, 6%). Participants with a higher pannus grade preoperatively experienced both a greater reduction in pannus severity (P < .0001) and a higher incidence of pannus-related symptoms (P = .002) postoperatively. Changes in pannus severity occurred during the first 24 months after bariatric surgery; mean pannus severity remained unchanged beyond 24 months. CONCLUSIONS: Severely obese adolescents who undergo bariatric surgery often present with an abdominal pannus at the time of surgery with associated symptoms. Higher preoperative pannus grade is associated with more pannus related symptoms after surgery. Counseling about need for body contouring surgery should be considered in this group.

Thirty-Year Risk of Cardiovascular Disease Events in Adolescents with Severe Obesity.

OBJECTIVE: Quantifying risk for cardiovascular disease (CVD) events among adolescents is difficult owing to the long latent period between risk factor development and disease outcomes. This study examined the 30-year CVD event risk among adolescents with severe obesity treated with and without metabolic and bariatric surgery (MBS), compared with youths with moderate obesity, overweight, or normal weight. METHODS: Cross-sectional and longitudinal comparisons of five frequency-matched (age and diabetes status) groups were performed: normal weight (n = 247), overweight (n = 54), obesity (n = 131), severe obesity without MBS (n = 302), and severe obesity undergoing MBS (n = 215). A 30-year CVD event score developed by the Framingham Heart Study was the primary outcome. Data are mean (SD) with differences between time points for MBS examined using linear mixed models. RESULTS: Preoperatively, the likelihood of CVD events was higher among adolescents undergoing MBS (7.9% [6.7%]) compared with adolescents with severe obesity not referred for MBS (5.5% [4.0%]), obesity (3.9% [3.0%]), overweight (3.1% [2.4%]), and normal weight (1.8% [0.8%]; all P < 0.001). At 1 year after MBS, event risk was significantly reduced (7.9% [6.7%] to 4.0% [3.4%], P < 0.0001) and was sustained for up to 5 years after MBS (P < 0.0001, all years vs. baseline). CONCLUSIONS: Adolescents with severe obesity are at elevated risk for future CVD events. Following MBS, the predicted risk of CVD events was substantially and sustainably reduced.

Stenting in Non-Small Cell Lung Cancer: How Does It Affect the Outcomes?

OBJECTIVE: Approximately 30% of lung cancer patients develop central airway obstruction (CAO) that remarkably shortens survival. There is little data about the benefits of stenting within this heterogeneous patient group. Our objective was to review their overall survival (OS) and their risk of hospitalization versus patients who did not have lesions requiring stent placement. METHODS: We retrospectively reviewed charts of 171 non-small cell lung cancer (NSCLC) patients who underwent bronchoscopy in the University of Cincinnati Cancer Center from the year 2011 to 2013. Twenty-five patients with advanced lung cancer were evaluated by interventional pulmonology service for endobronchial stent placement for CAO. Eight patients did not require placement of a stent and 17 had obstructive lesions that required stenting by interventional pulmonology. RESULTS: Demographical parameters such as age and gender did not have a significant impact on the risk of hospitalization or OS of both groups of patients, however, those whose lesions did not mandate stent placement had significantly lower odds of hospitalization compared to patients with CAO requiring a stent (OR: 15.913, 95% CI: 1.211-209.068, P = 0.0352). Patients with advanced NSCLC and CAO that required stent placement had an OS of 13.9 m [3.9-19.9 m] compared to an OS of 23.9 m for patients with CAO not requiring a stent. We found out that patients with less severe CAO have lower odds of hospitalization and better OS compared to patients with CAO mandating stent placement. CONCLUSION: CAO patients with interventional pulmonology (IP) evaluation and management in addition, may have improved OS suggesting that IP consultation might offer both improvement in quality of life and overall survival to patients with advanced NSCLC and CAO. 
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Body contouring in adolescents after bariatric surgery.

BACKGROUND: Bariatric surgery leads to sustained weight loss and resolution of obesity-associated co-morbidities in severely obese adolescents. However, one consequence of massive weight loss is excess skin and soft tissue. Many details regarding the timing, outcomes, and barriers associated with body contouring surgery (BCS) in youth who have undergone bariatric surgery are unknown. OBJECTIVES: Describe the incidence and effect of BCS following bariatric surgery among adolescents. SETTING: University Hospitals. METHODS: Teen-Longitudinal Assessment of Bariatric Surgery is a prospective multi-institutional study of 242 adolescents who underwent bariatric surgery from 2007 to 2012. Utilization of BCS was analyzed in this population with comparison of anthropometrics and excess skin-related symptoms between those who did and those who did not undergo BCS. RESULTS: Among the 198 study participants with BCS data available, 25 (12.6%) underwent 41 body contouring procedures after bariatric surgery. The most common BCS was panniculectomy (n = 23). Presence of pannus-related symptoms at baseline and the magnitude of weight loss within the first year after bariatric surgery were independently associated with subsequent panniculectomy (P = .04 and P = .03, respectively). All adolescents who underwent panniculectomy experienced resolution of pannus-related symptoms. At 5 years after bariatric surgery, 74% of those who did not undergo panniculectomy reported an interest in the procedure, and 58% indicated that cost/insurance coverage was the barrier to obtaining BCS. CONCLUSION: Few adolescents who underwent bariatric surgery later underwent BCS procedures. Panniculectomy effectively treated pannus-related symptoms. Disparities in access to surgical care for adolescents who desire BCS warrants further investigation.

Effect of Surgical Versus Medical Therapy on Diabetic Kidney Disease Over 5 Years in Severely Obese Adolescents With Type 2 Diabetes.

OBJECTIVE: To compare diabetic kidney disease (DKD) rates over 5 years of follow-up in two cohorts of severely obese adolescents with type 2 diabetes (T2D) undergoing medical or surgical treatment for T2D. RESEARCH DESIGN AND METHODS: A secondary analysis was performed of data collected from obese participants of similar age and racial distribution enrolled in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and the Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) studies. Teen-LABS participants underwent metabolic bariatric surgery (MBS). TODAY participants were randomized to metformin alone or in combination with rosiglitazone or intensive lifestyle intervention, with insulin therapy given for glycemic progression. Glycemic control, BMI, estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), and prevalence of hyperfiltration (eGFR ≥135 mL/min/1.73 m2) and elevated UAE (≥30 mg/g) were assessed annually. RESULTS: Participants with T2D from Teen-LABS (n = 30, mean ± SD age, 16.9 ± 1.3 years; 70% female; 60% white; BMI 54.4 ± 9.5 kg/m2) and TODAY (n = 63, age 15.3 ± 1.3 years; 56% female; 71% white; BMI 40.5 ± 4.9 kg/m2) were compared. During 5 years of follow-up, hyperfiltration decreased from 21% to 18% in Teen-LABS and increased from 7% to 48% in TODAY. Elevated UAE decreased from 27% to 5% in Teen-LABS and increased from 21% to 43% in TODAY. Adjusting for baseline age, sex, BMI, and HbA1c, TODAY participants had a greater odds of hyperfiltration (odds ratio 15.7 [95% CI 2.6, 94.3]) and elevated UAE (27.3 [4.9, 149.9]) at 5 years of follow-up. CONCLUSIONS: Compared with MBS, medical treatment of obese youth with T2D was associated with a higher odds of DKD over 5 years.

Musculoskeletal Pain, Physical Function, and Quality of Life After Bariatric Surgery.

OBJECTIVES: To evaluate the longitudinal effects of metabolic and bariatric surgery (MBS) on the prevalence of musculoskeletal and lower extremity (LE) pain, physical function, and health-related quality of life. METHODS: The Teen Longitudinal Assessment of Bariatric Surgery study (NCT00474318) prospectively collected data on 242 adolescents undergoing MBS at 5 centers over a 3-year follow-up. Joint pain and physical function outcomes were assessed by using the Health Assessment Questionnaire Disability Index, Impact of Weight on Quality of Life - Kids, and the Short Form 36 Health Survey. Adolescents with Blount disease (n = 9) were excluded. RESULTS: Prevalent musculoskeletal and LE pain were reduced by 40% within 12 months and persisted over 3 years. Adjusted models revealed a 6% lower odds of having musculoskeletal pain (odds ratio = 0.94, 95% confidence interval: 0.92-0.99) and a 10% lower odds of having LE pain (odds ratio = 0.90, 95% confidence interval: 0.86-0.95) per 10% reduction of BMI. The prevalence of poor physical function (Health Assessment Questionnaire Disability Index score >0) declined from 49% to <20% at 6 months (P < .05), Physical comfort and the physical component scores, measured by the Impact of Weight on Quality of Life - Kids and the Short Form 36 Health Survey, improved at 6 months postsurgery and beyond (P < .01). Poor physical function predicted persistent joint pain after MBS. CONCLUSIONS: Joint pain, impaired physical function, and impaired health-related quality of life significantly improve after MBS. These benefits in patient-reported outcomes support the use of MBS in adolescents with severe obesity and musculoskeletal pain and suggest that MBS in adolescence may reverse and reduce multiple risk factors for future joint disease.

Sex Hormone Phenotypes in Young Girls and the Age at Pubertal Milestones.

CONTEXT: The age of pubertal onset is influenced by many variables in young girls. Previous studies have not examined sex hormones longitudinally around the time of breast development and their relationship to pubertal onset. OBJECTIVE: We sought to use an unbiased statistical approach to identify phenotypes of sex hormones in young girls and examine their relationship with pubertal milestones. DESIGN AND SETTING: Longitudinal observational study. PARTICIPANTS AND MAIN OUTCOME MEASURES: In 269 girls, serum concentrations of steroid sex hormones [estradiol (E2), estrone, testosterone, and dehydroepiandrosterone sulfate] were measured by HPLC-mass spectrometry at time points before, at, and after thelarche. Girls were classified into four hormone phenotypes using objective principal components and cluster analyses of longitudinal hormone data. The association between the identified phenotypes and age of pubertal milestones was estimated using Cox proportional hazards modeling. RESULTS: Mean ages at thelarche, pubarche, and menarche were 9.02, 9.85, and 12.30 years, respectively. Girls with low levels of all four hormones, phenotype 3b, were youngest at thelarche (8.67 years); those in phenotype 2, with the highest E2 levels and E2 surge 6 months after thelarche, were youngest at menarche (11.87 years) with shortest pubertal tempo. When controlling for race, maternal age of menarche, caregiver education, and body mass, different phenotypes were associated with the age of pubertal events. CONCLUSIONS: Hormone phenotypic clustering can identify clinically relevant subgroups with differing ages of thelarche, pubarche, and menarche. These findings may enhance the understanding of timing of pubertal milestones and risk of adult disease.

Five-Year Outcomes of Gastric Bypass in Adolescents as Compared with Adults.

BACKGROUND: Bariatric surgery results in weight loss and health improvements in adults and adolescents. However, whether outcomes differ according to the age of the patient at the time of surgery is unclear. METHODS: We evaluated the health effects of Roux-en-Y gastric bypass in a cohort of adolescents (161 patients enrolled from 2006 through 2012) and a cohort of adults (396 patients enrolled from 2006 through 2009). The two cohorts were participants in two related but independent studies. Linear mixed and Poisson mixed models were used to compare outcomes with regard to weight and coexisting conditions between the cohorts 5 years after surgery. The rates of death and subsequent abdominal operations and selected micronutrient levels (up to 2 years after surgery) were also compared between the cohorts. RESULTS: There was no significant difference in percent weight change between adolescents (-26%; 95% confidence interval [CI], -29 to -23) and adults (-29%; 95% CI, -31 to -27) 5 years after surgery (P = 0.08). After surgery, adolescents were significantly more likely than adults to have remission of type 2 diabetes (86% vs. 53%; risk ratio, 1.27; 95% CI, 1.03 to 1.57) and of hypertension (68% vs. 41%; risk ratio, 1.51; 95% CI, 1.21 to 1.88). Three adolescents (1.9%) and seven adults (1.8%) died in the 5 years after surgery. The rate of abdominal reoperations was significantly higher among adolescents than among adults (19 vs. 10 reoperations per 500 person-years, P = 0.003). More adolescents than adults had low ferritin levels (72 of 132 patients [48%] vs. 54 of 179 patients [29%], P = 0.004). CONCLUSIONS: Adolescents and adults who underwent gastric bypass had marked weight loss that was similar in magnitude 5 years after surgery. Adolescents had remission of diabetes and hypertension more often than adults. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number, NCT00474318.).

Pattern of Marginal Local Failure in a Phase II Trial of Neoadjuvant Chemotherapy and Stereotactic Body Radiation Therapy for Resectable and Borderline Resectable Pancreas Cancer.

OBJECTIVES: The main objectives of this study were to prospectively evaluate the safety and efficacy of stereotactic body radiation therapy (SBRT) in the neoadjuvant setting for resectable or borderline resectable pancreatic cancer. MATERIALS AND METHODS: Eighteen patients were enrolled from November 2014 to June 2017. Following 3 cycles of chemotherapy, SBRT was delivered to the tumor and abutting vessel and a 3 mm planning target volume (PTV) margin to 33 Gy (6.6 Gy×5) with an optional elective PTV to 25 Gy (5 Gy×5) customized to the nodal space and mesenteric vessels. The primary endpoint is ≥grade 3 acute and late gastrointestinal toxicity. RESULTS: Fifteen patients had borderline resectable tumors due to arterial abutment (n=7) or superior mesenteric vein encasement (n=8); 3 patients had resectable tumors. There were no ≥grade 3 acute or late gastrointestinal events. Following SBRT, surgery was performed in 12 patients (67%) with 11 (92%) R0 resections. The median overall survival and progression-free survival was 21 months (95% CI: 18-29) and 11 months (95% CI: 8.4-16). Progression occurred in 83% (10/12) of resected patients (distant [n=4, 40%], local-only [n=4, 40%], and local and distant [n=2, 20%]). The cumulative incidence of local failure (LF) at 12 months from resection was 50% (95% CI: 20-80). All LF were outside to the PTV33. CONCLUSIONS: Neoadjuvant SBRT was well tolerated, however LFs were predominantly observed outside the PTV33 volume that would have been covered with conventional RT volumes. The durability of local control after SBRT in the neoadjuvant setting merits examination relative to chemoradiation before incorporation into routine practice.

Childhood polybrominated diphenyl ether (PBDE) serum concentration and reading ability at ages 5 and 8 years: The HOME Study.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) exist extensively in the environment and human beings. PBDE concentrations are higher in children than adults. A previous study found that prenatal PBDE exposure was associated with decreased reading skills in children; however, evidence is limited on the potential impact of childhood exposure to PBDEs. The study examined the association between childhood PBDE exposures and reading ability in children at ages 5 and 8 years. METHODS: The study included 230 children from an ongoing prospective pregnancy and birth cohort study, the Health Outcomes and Measures of Environment (HOME) Study, conducted in Cincinnati, Ohio. Children's serum concentrations of eleven PBDE congeners were measured at 1, 2, 3, 5, and 8 years. The Woodcock-Johnson Tests of Achievement - III and the Wide Range Achievement Test - 4 were administered to assess children's reading skills at ages 5 and 8 years, respectively. We used multiple informant models to examine the associations between repeated measures of PBDEs and reading scores at ages 5 and 8 years. We also estimated the ßs and 95% CIs of the association of PBDE measure at each age by including interaction terms between PBDE concentrations and child age in the models. RESULTS: All childhood BDE-153 concentrations were inversely associated with reading scores at 5 and 8 years, but associations were not statistically significant after covariate adjustment. For example, a 10-fold increase in BDE-153 concentrations at ages 3 and 5 years was associated with a -5.0 (95% confidence interval (CI): -11.0, 1.0) and -5.5 (95% CI: -12.5, 1.4) point change in Basic Reading score at age 5 years, respectively. Similarly, the estimates for Brief Reading score at age 5 years were -4.5 (95% CI: -10.5, 1.5) and -5.2 (95% CI: -12.2, 1.7) point changes, respectively. Serum concentration of BDE-47, -99, -100, and Sum4PBDEs (sum of BDE-47, 99, 100, and 153) at every age were inversely associated with reading scores at ages 5 and 8 years in unadjusted analyses. While the adjusted estimates were much attenuated and became non-significant, the direction of most of the associations was not altered. CONCLUSION: Our study has shown a suggestive but non-significant trend of inverse associations between childhood PBDE serum concentrations, particularly BDE-153, and children's reading skills. Future studies with a larger sample size are needed to examine these associations.

Identification of sex-specific DNA methylation changes driven by specific chemicals in cord blood in a Faroese birth cohort.

Faroe islanders consume marine foods contaminated with methylmercury (MeHg), polychlorinated biphenyls (PCBs), and other toxicants associated with chronic disease risks. Differential DNA methylation at specific CpG sites in cord blood may serve as a surrogate biomarker of health impacts from chemical exposures. We aimed to identify key environmental chemicals in cord blood associated with DNA methylation changes in a population with elevated exposure to chemical mixtures. We studied 72 participants of a Faroese birth cohort recruited between 1986 and 1987 and followed until adulthood. The cord blood DNA methylome was profiled using Infinium HumanMethylation450 BeadChips. We determined the associations of CpG site changes with concentrations of MeHg, major PCBs, other organochlorine compounds [hexachlorobenzene (HCB), p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and p,p'-dichlorodiphenyltrichloroethane], and perfluoroalkyl substances. In a combined sex analysis, among the 16 chemicals studied, PCB congener 105 (CB-105) exposure was associated with the majority of differentially methylated CpG sites (214 out of a total of 250). In female-only analysis, only 73 CB-105 associated CpG sites were detected, 44 of which were mapped to genes in the ELAV1-associated cancer network. In males-only, methylation changes were seen for perfluorooctane sulfonate, HCB, and p,p'-DDE in 10,598, 1,238, and 1,473 CpG sites, respectively, 15% of which were enriched in cytobands of the X-chromosome associated with neurological disorders. In this multiple-pollutant and genome-wide study, we identified key epigenetic toxicants. The significant enrichment of specific X-chromosome sites in males implies potential sex-specific epigenome responses to prenatal chemical exposures.

Pulmonary sarcomatoid carcinoma: University of Cincinnati experience.

OBJECTIVES: To review the outcomes of treatment in patients with pulmonary sarcomatoid carcinoma (PSC) treated at the University of Cincinnati Medical Center (UCMC). RESULTS: There was no significant difference in survival of patients treated with chemotherapy alone (median, 256 days) compared to patients not undergoing treatment (median, 205.5 days). Patients who underwent surgery and adjuvant chemotherapy showed a trend in improvement of survival (median, 457.6 days). Patients requiring only surgery had the longest OS of 713.5 days. CONCLUSIONS: Systemic chemotherapy alone did not improve survival in patients with PSC. Surgery provides the greatest overall survival benefit and adjuvant chemotherapy may also improve survival. METHODS: From 2000 to 2014, twenty-five patients with pathologically confirmed PSC were treated at UCMC. The outcomes were retrospectively analyzed by treatment with overall survival (OS) as the endpoint.