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Background Preoperative parathyroid imaging guides surgeons during parathyroidectomy. This study evaluates the clinical impact of 18F-fluorocholine positron emission tomography for preoperative parathyroid localization on patients with primary hyperparathyroidism. Methods Patients with primary hyperparathyroidism and indications for parathyroidectomy had simultaneous 18F-fluorocholine positron emission tomography imaging/magnetic resonance imaging. In patients who underwent subsequent parathyroidectomy, cure was based on lab values at least 6 months after surgery. Location-based sensitivity and specificity of 18F-fluorocholine positron emission tomography imaging was assessed using 3 anatomic locations (left neck, right neck, and mediastinum), with surgery as the gold standard. Results In 101 patients, 18F-fluorocholine positron emission tomography localized at least 1 candidate lesion in 93% of patients overall and in 91% of patients with previously negative imaging, leading to a change in preoperative strategy in 60% of patients. Of 76 patients who underwent parathyroidectomy, 58 (77%) had laboratory data at least 6 months postoperatively, with 55/58 patients (95%) demonstrating cure. 18F-fluorocholine positron emission tomography successfully guided curative surgery in 48/58 (83%) patients, compared with 20/57 (35%) based on ultrasound and 13/55 (24%) based on sestamibi. In a location-based analysis, sensitivity of 18F-fluorocholine positron emission tomography (88.9%) outperformed both ultrasound (37.1%) and sestamibi (27.5%), as well as ultrasound and sestamibi combined (47.8%). Conclusion Long-term results in the first cohort in the United States to use 18F-fluorocholine positron emission tomography for parathyroid localization confirm its utility in a challenging cohort, with better sensitivity than ultrasound or sestamibi.

Background Radiofrequency ablation is an alternative strategy for the management of benign thyroid conditions. We analyzed the proportion of patients who underwent thyroid surgery for benign conditions who would be potentially eligible for radiofrequency ablation. Methods We identified patients who underwent thyroid surgery from 2015 to 2019 at the study institution for Bethesda II cytopathology or toxic adenoma. Patients were considered potentially eligible for radiofrequency ablation if they had a dominant nodule >2 cm with or without compression symptoms, a dominant nodule Results Of 411 patients in total, 284 (69.1%) would be eligible to consider thyroid radiofrequency ablation. In the radiofrequency ablation–eligible group, 20 (7.0%) experienced voice change after surgery, and 2 (0.7%) were dissatisfied or concerned about their scar. In the radiofrequency ablation–eligible group, 70 patients (24.6%) had malignancy diagnosed by final pathology, and 23 patients (8.1%) had cancers that were equal to or larger than 1 cm in size. Conclusion Many patients who undergo surgery for benign thyroid disease could be considered for radiofrequency ablation as an alternative treatment modality. Given the rate of occult malignancy, optimal evaluation of nondominant nodules before radiofrequency ablation and long-term thyroid surveillance for patients who undergo radiofrequency ablation should be further studied.

Pulmonary sclerosing pneumocytoma (PSP) is a tumor of pneumocytic origin that is classified as a benign neoplasm. To date, aggressive behavior of this tumor has rarely been reported. Here, we describe a case of a 56-year-old woman with a huge, 19-cm PSP that resulted in mediastinal shift and showed microscopic endobronchial invasion and necrosis. The differential diagnosis included malignant mesenchymal tumors, such as solitary fibrous tumor; however, PSP was confirmed based on the characteristic thyroid transcription factor 1 positivity and membranous expression of Ki-67 on immunohistochemical staining of tumor cells.

Purpose Intensity-modulated radiotherapy (IMRT) allows for more precise treatment, reducing unwanted radiation to nearby structures. We investigated the safety and feasibility of IMRT for anaplastic ependymoma patients below 3 years of age. Materials and methods A total of 9 anaplastic ependymoma patients below 3 years of age, who received IMRT between October 2011 and December 2017 were retrospectively reviewed. The median equivalent dose in 2 Gy fractions was 52.0 Gy (range, 48.0 to 60.0 Gy). Treatment outcomes and neurologic morbidities were reviewed in detail. Results The median patient age was 20.9 months (range, 12.1 to 31.2 months). All patients underwent surgery. The rates of 5-year overall survival, freedom from local recurrence, and progression-free survival were 40.6%, 53.3%, and 26.7%, respectively. Of the 9 patients, 5 experienced recurrences (3 had local recurrence, 1 had both local recurrence and cerebrospinal fluid [CSF] seeding, and 1 had CSF seeding alone). Five patients died because of disease progression. Assessment of neurologic morbidity revealed motor dysfunction in 3 patients, all of whom presented with hydrocephalus at initial diagnosis because of the location of the tumor and already had neurologic deficits before radiotherapy (RT). Conclusion Neurologic morbidity is not caused by RT alone but may result from mass effects of the tumor and surgical sequelae. Administration of IMRT to anaplastic ependymoma patients below 3 years of age yielded encouraging local control and tolerable morbidities. High-precision modern RT such as IMRT can be considered for very young patients with anaplastic ependymoma.

This case series examines the presence of necrosis in adrenocortical carcinoma as a diagnostic and prognostic indicator.

Chondroradionecrosis (CRN) is an infrequent phenomenon after definitive RT. The clinical manifestation is usually difficult to distinguish from that of tumor recurrence; however, clinicians should be aware of the possibility of CRN.

Background From patient-reported surveys and individual interviews by health care providers, we attempted to identify the significant factors related to the improvement of distress and fatigue for cancer survivors by text analysis with machine learning techniques, as the secondary analysis using the single institute data from the Korean Cancer Survivorship Center Pilot Project. Methods Surveys and in-depth interviews from 322 cancer survivors were analyzed to identify their needs and concerns. Among the keywords in the surveys, including EQ-VAS, distress, fatigue, pain, insomnia, anxiety, and depression, distress and fatigue were focused. The interview transcripts were analyzed via Korean-based text analysis with machine learning techniques, based on the keywords used in the survey. Words were generated as vectors and similarity scores were calculated by the distance related to the text’s keywords and frequency. The keywords and selected high-ranked ten words for each keyword based on the similarity were then taken to draw a network map. Results Most participants were otherwise healthy females younger than 50 years suffering breast cancer who completed treatment less than 6 months ago. As the 1-month follow-up survey’s results, the improved patients were 56.5 and 58.4% in distress and fatigue scores, respectively. For the improvement of distress, dyspepsia (p = 0.006) and initial scores of distress, fatigue, anxiety, and depression (p p = 0.021), needs for rehabilitation (p = 0.035), initial score of fatigue (p p = 0.017), and participation in family care program (p = 0.022) were significant. For the text analysis, Stress and Fatigue were placed at the center of the keyword network map, and words were intricately connected. From the regression anlysis combined survey scores and the quantitative variables from the text analysis, participation in family care programs and mention of family-related words were associated with the fatigue improvement (p = 0.033). Conclusion Common symptoms and practical issues were related to distress and fatigue in the survey. Through text analysis, however, we realized that the specific issues and their relationship such as family problem were more complicated. Although further research needs to explore the hidden problem in cancer patients, this study was meaningful to use personalized approach such as interviews.

The incidence of thyroid cancer is on the rise, and this disease is projected to become the fourth leading type of cancer across the globe. From 1990 to 2013, the global age-standardized incidence rate of thyroid cancer increased by 20%. This global rise in incidence has been attributed to several factors, including increased detection of early tumours, the elevated prevalence of modifiable individual risk factors (for example, obesity) and increased exposure to environmental risk factors (for example, iodine levels). In this Review, we explore proven and novel hypotheses for how modifiable risk factors and environmental exposures might be driving the worldwide increase in the incidence of thyroid cancer. Although overscreening and the increased diagnosis of possibly clinically insignificant disease might have a role in certain parts of the world, other areas could be experiencing a true increase in incidence due to elevated exposure risks. In the current era of personalized medicine, national and international registry data should be applied to identify populations who are at increased risk for the development of thyroid cancer.

Energy devices are important instruments in an endocrine surgeon’s toolbox because glandular organs are well vascularized and tend to bleed intraoperatively. Currently, energy devices most often used in endocrine surgery fall into two major categories: bipolar vessel sealing and ultrasonic. In current research, these energy devices have demonstrated similar rates of postoperative hematoma and injury to the parathyroid glands and recurrent laryngeal nerve, compared to traditional suture ligation. And more recently, in addition to bipolar and ultrasonic devices, radiofrequency ablation has emerged as a potential option for benign thyroid nodules and recurrent thyroid cancer.

Purpose This study aimed to investigate whether enlarged perivascular spaces (ePVS) within the basal ganglia (BG) or centrum semiovale (CSO) aggravate in patients with aneurysmal subarachnoid hemorrhage (aSAH). Methods We retrospectively evaluated 139 patients who had undergone brain magnetic resonance imaging (MRI) within 1 month of aSAH occurrence from January 2007 to November 2018. Follow-up brain MRI of 99 patients were available. We scored ePVS in the BG and CSO on a score of 0-4 (0 = no ePVS, 4 ≥ 40 ePVS) on initial and follow-up T2-weighted MRI. Aggravation of ePVS was defined as an ePVS score increase of ≥ 1 on follow-up MRI compared to the initial score. We compared the characteristics between patients with and without aggravation of ePVS and investigated associated variables using logistic regression. Results Aggravation of ePVS in the CSO and BG was noted in 31 (31.3%) and 6 (6.1%) patients, respectively. After adjusting for age, sex, and the MRI follow-up period, aggravation of ePVS in the CSO was independently associated with a high Fisher grade (p = 0.007) and high burden of initial ePVS in the CSO (p = 0.049). Conclusion Aggravation of ePVS, particularly those in the CSO, had occurred in the long-term follow-up of aSAH patients. This was independently associated with a high burden of aSAH. The amount of subarachnoid blood might have aggravated the drainage of interstitial fluid through glymphatic dysfunction.

Objective To validate the revised 2018 International Federation of Gynecologic and Obstetrics (FIGO) staging system in patients who underwent diagnostic magnetic resonance imaging (MRI) and radiotherapy (RT) for locally advanced cervix cancer. Methods We analyzed 677 patients who were diagnosed with pelvic MRI and treated with definitive (chemo-)RT for locally advanced cervix cancer (stage IB2/IIA2-IVA or N+) between 1992 and 2018. Patients were classified according to 2009 and 2018 FIGO staging, and survival outcomes were compared. We developed a nomogram to improve prediction of progression-free survival (PFS). Results Pelvic and paraaortic lymph nodes were positive in 331 (48.9%) and 78 (11.5%) patients, respectively. At a median follow-up of 77.9 months, the 5-year PFS was 83.5%, 65.2%, 71.0%, 60.6%, 37.6% and 38.9% for IB, IIA, IIB, IIIA, IIIB and IVA according to FIGO 2009 and 88.9%, 60.0%, 73.8%, 66.7%, 36.3%, 68.9%, 43.6%, and 38.9% for IB, IIA, IIB, IIIA, IIIB, IIIC1, IIIC2, and IVA according to FIGO 2018, respectively. Survival of stage IIIC cervix cancer depended on the local extent of the tumor: the 5-year PFS of T1, T2, and T3 stages were 80.3%, 73.9%, and 45.5% for IIIC1 and 100%, 44.9%, and 23.4% for IIIC2. Histology, tumor size, node metastasis, FIGO 2009, and treatment modality were independent prognostic factors in the Cox regression analysis, and the nomogram incorporating these factors outperformed FIGO 2009 and FIGO 2018 (AUC 0.718 vs. 0.616 vs. 0.594). Conclusions FIGO 2018 revision was associated with heterogenous outcomes among stage III cervix cancer patients. Our nomogram can assist the FIGO system in predicting PFS after definitive RT.

Users of social media often share their feelings or emotional states through their posts. In this study, we developed a deep learning model to identify a user’s mental state based on his/her posting information. To this end, we collected posts from mental health communities in Reddit. By analyzing and learning posting information written by users, our proposed model could accurately identify whether a user’s post belongs to a specific mental disorder, including depression, anxiety, bipolar, borderline personality disorder, schizophrenia, and autism. We believe our model can help identify potential sufferers with mental illness based on their posts. This study further discusses the implication of our proposed model, which can serve as a supplementary tool for monitoring mental health states of individuals who frequently use social media.

Upon liver intoxication with malnutrition or high-fat diet feeding, fibrinogen is synthesized by hepatocytes and secreted into the blood in human and mouse. Its primary function is to occlude blood vessels upon damage and thereby stop excessive bleeding. High fibrinogen levels may contribute to the development of pathological thrombosis, which is one mechanism linking fatty liver disease with cardiovascular disease. Our previous results present ERRγ as key regulator of hepatocytic fibrinogen gene expression in human. In a therapeutic approach, we now tested ERRγ inverse agonist GSK5182 as regulator of fibrinogen levels in mouse hyperfibrinogenemia caused by diet-induced obesity and in mouse hepatocytes. ACEA, a CB1R agonist, up-regulated transcription of mouse fibrinogen via induction of ERRγ, whereas knockdown of ERRγ attenuated the effect of ACEA (10 µM) on fibrinogen expression in AML12 mouse hepatocytes. Deletion analyses of the mouse fibrinogen γ (FGG) gene promoter and ChIP assays revealed binding sites for ERRγ on the mouse FGG promoter. ACEA or adenovirus ERRγ injection induced FGA, FGB and FGG mRNA and protein expression in mouse liver, while ERRγ knockdown with Ad-shERRγ attenuated ACEA-mediated induction of fibrinogen gene expression. Moreover, mice maintained on a high-fat diet (HFD) expressed higher levels of fibrinogen, whereas cannabinoid receptor type 1 (CB1R)-KO mice fed an HFD had nearly normal fibrinogen levels. Finally, GSK5182 (40 mg/kg) strongly inhibits the ACEA (10 mg/kg) or HFD-mediated induction of fibrinogen level in mice. Taken together, targeting ERRγ with its inverse agonist GSK5182 represents a promising therapeutic strategy for ameliorating hyperfibrinogenemia.

Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor in children, with current evidence limited to single-center studies. We examined treatment and clinical outcomes for pediatric and adult SPN with a national data set.The 2004 to 2013 National Cancer Data Base was queried to identify all patients diagnosed with SPN. The cohort was stratified by age (pediatric and adult) defined as below 18 years and 18 years and above, respectively. Baseline characteristics and unadjusted outcomes were compared.We identified 21 pediatric and 348 adult patients with SPN. Both groups displayed similar demographic composition. Patients were commonly female (90.5% [pediatric] vs. 85.9% [adult], P=0.56) and white (66.7% vs. 68.3%, P=0.74). Tumor location was similar between adults and children. Median tumor size was similar between children and adults (5.9 vs. 4.9 cm, P=0.41). Treatment strategies did not vary between groups. Partial pancreatectomy was the most common resection strategy (71.4% vs. 53.1%, P=0.80). Both groups experienced low mortality (0.0% vs. 0.7% at 5 y, P=0.31).This study provides the largest comparison of pediatric and adult SPN to date. Children with SPN have similar disease severity at presentation, receive similar treatments, and demonstrate equivalent postoperative outcomes compared with their adult counterparts.

Background Our study compares 30-day vs. 90-day mortality following colorectal cancer surgery (CRS), and examines hospital performance ranking based on this assessment. Methods Mortality rates were compared between 30 vs. 90 days following CRS for patients with stage I-III colorectal cancers from the National Cancer Database (2004–2012). Risk-adjusted hierarchical regression models evaluated hospital performance based on mortality. Hospitals were ranked into top (10%), middle (80%), and lowest (10%) performance groups. Results Among 185,464 patients, 90-day mortality was nearly double the 30-day mortality (4.4% vs. 2.5%). Following risk adjustment 176 hospitals changed performance ranking: 39% in the top 30-day mortality group changed ranking to the middle group; 37% of hospitals in the lowest 30-day group changed ranking to the middle 90-day group. Conclusions Evaluation of hospital performance based on 30-day mortality is associated with misclassification for 15% of hospitals. Ninety-day mortality may be a better quality metric in oncologic CRS.

Purpose Resection of congenital pulmonary airway malformations (CPAMs) is often performed to reduce the risk of recurrent infection and malignant transformation. However, there is substantial variation in the timing of resection. This study was performed to determine the association of age and weight on outcomes following elective resection of CPAMs. Methods The American College of Surgeons National Surgical Quality Improvement Program-Pediatric database from 2012 to 2014 was queried for infants undergoing elective resection of a CPAM. Infants were categorized based on age (0–3 months, 3–6 months, 6–9 months, 9–12 months, and > 12 months) and weight (0–5 kg, 5–10 kg, and > 10 kg). Groups were compared for baseline characteristics and outcomes including a morbidity composite of pneumonia, reintubation, ventilator days > 0, reoperation, readmission, hospital length of stay > 7 days, and mortality. Results A total of 311 infants met study criteria. The morbidity composite was significantly more common among infants 3 months of age (31.3% vs. 15.6%, p = 0.01) and among infants 5 kg (37.5% vs. 15.8%, p Conclusions Infants should be observed until three months of age and a weight of five kilograms prior to elective resection of CPAMs. Level of evidence Level III.

Aim To examine the overall survival differences of neoadjuvant therapy modalities: no therapy, chemotherapy alone, radiation alone, and chemoradiation in a large cohort of patients with locally advanced rectal cancer. Method Adults with clinical stage II and III rectal adenocarcinoma were selected from the National Cancer Database and grouped by type of neoadjuvant therapies received: no therapy, chemotherapy only, radiotherapy only, or chemoradiation. Multivariable regression methods were used to compare adjusted differences in perioperative outcomes and overall survival. Results Among 32978 patients included, 9714 (29.5%) received no neoadjuvant therapy, 890 (2.7%) chemotherapy only, 1170 (3.5%) radiotherapy only, and 21204 (64.3%) chemoradiation. Compared to no therapy, chemotherapy or radiotherapy alone was not associated with any adjusted differences in surgical margin positivity, permanent colostomy rate, or overall survival (all p > 0.05). With adjustment, neoadjuvant chemoradiation vs. no therapy was associated with a lower likelihood of surgical margin positivity (OR 0.74, p < 0.001), decreased rate of permanent colostomy (OR 0.77, p < 0.001), and overall survival (HR 0.79, p < 0.001). When compared to chemotherapy or radiotherapy alone, chemoradiation remain associated with improved overall survival (vs. chemotherapy alone: HR 0.83, p = 0.04; vs. radiotherapy alone: HR 0.83, p < 0.019). Conclusions Neoadjuvant chemoradiation, not chemotherapy or radiotherapy alone, is important for sphincter preservation, R0 resection, and survival for patients with locally advanced rectal cancer. Despite this finding, one-third of patients in the United States with locally advanced rectal cancer fail to receive stage-appropriate chemoradiation. This article is protected by copyright. All rights reserved.

At our institution, a high proportion of children with onychocryptosis (ingrown toenail) requiring surgical intervention were noted to have a history of hematopoietic stem cell transplantation (HSCT). We analyzed the characteristics of patients who underwent surgical intervention for onychocryptosis and examined our institutional HSCT database to determine if an association exists between onychocryptosis and HSCT.Surgical cases for onychocryptosis performed from 2000 to 2012 were identified. Nine demographic, clinical, and perioperative variables for both patients with and without prior HSCT were assessed. In a separate analysis, the institutional HSCT database was then queried to identify the prevalence and clinical characteristics associated with onychocryptosis after HSCT.We identified 17 children who had undergone surgical management of onychocryptosis, of which 8 (47.1%) had previous HSCT. Children who had undergone HSCT had an aggressive form of onychocryptosis with 50.0% having bilateral great toe and nail edge involvement and 37.5% having a recurrence. In HSCT cohort analysis of 1069 children, 91 (8.5%) had onychocryptosis. Male sex, non-black race, acute graft versus host disease, and increasing age at transplantation were independently associated with onychocryptosis.HSCT is strongly associated with onychocryptosis requiring surgical intervention. Children with a history of HSCT may also have more aggressive toenail disease, with higher rates of surgical intervention, bilateral ingrown toenails, recurrence, and need for return to the operating room. Clinicians should perform careful screening and early treatment in these patients.

Objective:To determine the impact of race and insurance on use of minimally invasive (MIS) compared with open techniques for rectal cancer in the United States.Background:Race and socioeconomic status have been implicated in disparities of rectal cancer treatment.Methods:Adults undergoing MIS (lapar

Hypoalbuminemia is associated with adverse surgical outcomes. A minimum threshold and the impact of incrementally decreasing albumin remain undefined for colorectal surgery patients. The 2011–2013 National Surgical Quality Improvement Program (NSQIP) dataset was queried for patients undergoing elective colorectal surgery. Multivariable regression analyses with restricted cubic splines (RCS) were used to examine the adjusted association between preoperative serum albumin level and the incidence of complications and to establish an optimal threshold. RCS allows for flexible evaluation in multivariable models without having to assume a specific relationship a priori. Sixteen thousand one hundred forty-five patients met study criteria. RCS analysis demonstrated an inflection point at serum albumin level of 3.9 mg/dL. Patients with preoperative albumin

Purpose As the role of extracorporeal life support (ECLS) continues to evolve in the adult and pediatric populations, smaller studies and case reports have described successful use of ECLS in specific groups of pediatric trauma patients. To further define the role of ECLS in pediatric trauma, we examined indications and outcomes for use of ECLS in injured children using a large national database. Methods All trauma patients ≤18years old were identified from the 2007 to 2011 National Trauma Data Bank. We collected patient demographics, mechanism of injury, injury severity, use of ECLS, and survival to discharge. Children undergoing ECLS were compared to those who did not undergo ECLS, using a 3:1 propensity matched analysis to compare outcomes between ECLS and non-ECLS patients with similar injury patterns. Results Of 589,895 pediatric trauma patients identified, 36 patients underwent ECLS. Within the ECLS cohort, 21/36 (58%) survived, and 10/36 (28%) were discharged directly home. Most ECLS patients were between 15 and 18years 20/36 (56%). Mechanisms of injury (MOI) resulting in ECLS use included: motor vehicle collision (MVC) 16/36 (44%), gunshot wound (GSW) 6/36 (17%), burns 6/36 (17%), and drowning/suffocation (D/S) 5/36 (14%). Among the ECLS cohort, survival varied by MOI from 75% in D/S to 56% in MVC and 33% in GSW and was 55% in patients with significant head injuries. Using propensity analysis for matched injury patterns, survival for ECLS and non-ECLS patients was similar (58% vs. 65%, p =0.61). Conclusions In the largest study to date of ECLS support in pediatric trauma patients, we found encouraging survival rates to discharge, comparable to patients not undergoing ECLS with similar injuries. These results support further use and focused research of ECLS in pediatric trauma, including drowning, burn, and MVC victims and those with significant head injuries. Level of evidence Level III; treatment study.

Background/purpose There are limited data identifying risk factors for nodal metastasis in children with differentiated thyroid cancer. Methods The 1998–2011 Surveillance, Epidemiology, and End Results Program database was queried for patients ≤18years of age diagnosed with differentiated thyroid cancer who underwent nodal examination. Patients were grouped by absence or presence of nodal metastasis. Multivariable logistic regression methods were used to identify independent risk factors for nodal metastasis. Results In total, 1075 children met study criteria: 734 (68%) had nodal metastases, while 341 (32%) did not. After adjustment, risk factors for nodal metastasis included larger tumor size (1.1–2cm: odds ratio [OR] 2.02, 95% confidence interval [CI] 1.22–3.34, p=0.006; 2.1–4cm: OR 3.37, 95% CI 2.03–5.60, p 4cm: OR 3.39, 95% CI 1.69–6.81, p=0.001), extrathyroidal extension (OR 7.28, 95% CI 4.07–13.01, p Conclusions Increasing tumor size, extrathyroidal extension, and multifocal disease are independent factors associated with nodal metastases in pediatric differentiated thyroid cancer. If these risk factors are present, children with differentiated thyroid cancer should undergo careful preoperative evaluation for evidence of lateral cervical lymph node metastases, and the central compartment should be evaluated intraoperatively, with consideration of central lymphadenectomy. Level of evidence Level III.

Although SREBP-1c regulates key enzymes required for hepatic de novo lipogenesis, the mechanisms underlying transcriptional regulation of SREBP-1c in pathogenesis of alcoholic fatty liver is still incompletely understood. In this study, we investigated the role of ERRγ in alcohol-mediated hepatic lipogenesis and examined the possibility to ameliorate alcoholic fatty liver through its inverse agonist. Hepatic ERRγ and SREBP-1c expression was increased by alcohol-mediated activation of CB1 receptor signaling. Deletion and mutation analyses of the Srebp-1c gene promoter showed that ERRγ directly regulates Srebp-1c gene transcription via binding to an ERR-response element. Overexpression of ERRγ significantly induced SREBP-1c expression and fat accumulation in liver of mice, which were blocked in Srebp-1c-knockout hepatocytes. Conversely, liver-specific ablation of ERRγ gene expression attenuated alcohol-mediated induction of SREBP-1c expression. Finally, an ERRγ inverse agonist, GSK5182, significantly ameliorates fatty liver disease in chronically alcohol-fed mice through inhibition of SREBP-1c-mediated fat accumulation. ERRγ mediates alcohol-induced hepatic lipogenesis by upregulating SREBP-1c expression, which can be blunted by the inverse agonist for ERRγ, which may be an attractive therapeutic strategy for the treatment of alcoholic fatty liver disease in human.

An inverse agonist of estrogen-related receptor-γ (ERRγ), an orphan nuclear receptor encoded by Esrrg, enhances sodium iodide symporter-mediated radioiodine uptake in anaplastic thyroid cancer (ATC) cells, thereby facilitating responsiveness to radioiodine therapy in vitro. We synthesized potent, selective, and orally bioavailable ERRγ-inverse agonists and evaluated their activity by analyzing in vitro pharmacology and absorption, distribution, metabolism, excretion, and toxicity profiles. X-ray crystallographic analysis of the ligand and ERRγ complex showed that 35 completely binds to the target protein (PDB 6A6K). Our results showed improved radioiodine avidity in ATC cells through compound 35-mediated upregulation of iodide-handling genes, leading to enhanced responsiveness to radioiodine therapy in vitro. Importantly, in vivo 124I-positron emission tomography/computed tomography imaging revealed that 35 increases radioiodine avidity in CAL62 tumors. Collectively, these results demonstrated that 35 can...

Homeodomain‑containing gene 10 (HOXC10) is a member of the homeobox transcription factors that plays an important role in the development of multicellular organisms. HOXC10 is overexpressed in a variety of human cancers, and recent studies have revealed that HOXC10 is upregulated in gastric cancer as well. However, its mechanism of action is not fully understood, thus, the role of HOXC10 was investigated in the present study in human gastric cancer. First, HOXC10 expression was revealed to be significantly increased in gastric cancer tissues compared to normal tissues (TCGA dataset), and HOXC10 upregulation was associated with decreased recurrence‑free survival in gastric cancer patients in a public gene expression dataset. HOXC10 promoted cell proliferation and metastasis in two gastric cancer cell lines (AGS and MKN74). Analyzing TCGA 450K DNA methylation dataset, it was revealed that HOXC10 CpG sites were hypomethylated in gastric cancer tissues. Bisulfite sequencing revealed that CpG sites in the HOXC10 first intronic region were hypomethylated in three gastric cancer tissues, and HOXC10 expression was increased in gastric cancer cell lines (AGS and SNU620) in response to 5‑azacytidine treatment. By RNA‑sequencing of AGS cells with ectopic HOXC10 expression, it was revealed that many genes were upregulated by HOXC10 overexpression. Among them, CST1 was predicted to be a HOXC10 direct target gene via prediction of HOXC10 binding sites from the JASPAR database. A chromatin immunoprecipitation assay revealed that HOXC10 directly bound to CST1 promoter regions. The present study proposes HOXC10 is a potential prognostic marker or therapeutic target in human gastric cancer.

Author(s): Graves, Claire E; Goyal, Neha; Levin, Anna; Nuno, Miriam A; Kim, Jina; Campbell, Michael J; Shen, Wen T; Gosnell, Jessica Erin; Roman, Sanziana; Sosa, Julie Ann; Duh, Quan-Yang; Suh, Insoo | Abstract: Abstract Background: The coronavirus (COVID-19) pandemic has led to rapid changes in our society and healthcare system. Cancer patients and survivors may be disproportionately affected by these changes, including decreased access to healthcare, increased infection risk, and economic challenges. We sought to determine the effects of the pandemic on thyroid cancer survivors’ quality of life. Methods: An anonymous web-based survey was administered in collaboration with ThyCa: Thyroid Cancer Survivors’ Association, consisting of questions about (1) demographics, (2) thyroid cancer clinical characteristics, (3) attitudes toward and impact of COVID-19, and (4) the Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item profile. The survey was linked on the ThyCa homepage. PROMIS measures were scored using item response theory models with a T-score metric relative to U.S. reference data via the HealthMeasures Scoring Service (https://www.healthmeasures.net). T-scores were analyzed using Mann-Whitney U, Wilcoxon signed-rank, Kruskal-Wallis, and Spearman’s rank correlation tests. Results: From 5/6/2020 - 10/8/2020, 505 participants accessed the survey, and all completed surveys by U.S.-based thyroid cancer survivors were analyzed (n=378, 75%). Mean age was 53 years, 89% were female, 90% were white, 74% had papillary thyroid cancer, 97% had surgery, and 70% received radioactive iodine. The vast majority agreed or strongly agreed (83%) that their lives were very different during COVID-19, as was the way they interacted with their doctors (79%). Less than half (43%) agreed or strongly agreed that they were satisfied with the amount of information from their doctor’s office regarding COVID-19 changes. Compared to previously-published PROMIS data for this population, T-scores were significantly higher in the domain of anxiety/fear (57.8 vs. 56.5, pl0.01) and lower for ability to participate in social roles and activities (46.2 vs. 48.1, pl0.01). Younger age was weakly correlated with greater anxiety/fear (Spearman’s rho=-0.38, pl0.01), and greater anxiety/fear was associated with pending treatment (pl0.01), lower cancer stage (p=0.01), and female sex (p=0.02). Conclusions: During the COVID-19 pandemic, thyroid cancer survivors reported increased anxiety/fear and decreased social participation. In our efforts to care for patients both physically and mentally as the pandemic continues, we must better understand their fears and concerns and improve communication about potential changes to their care.

Tumor-associated macrophages (TAMs) are predominantly associated with tumor growth. Colony-stimulating factor 1 receptor (CSF1R) acts as a key regulator of TAM survival and differentiation and is a molecular target for cancer therapies. Herein, novel CSF1R inhibitors were identified through a replacement strategy for the hinge-binding moiety. The introduction of imidazo[1,2-a]pyridine (49) or pyrazolo[1,5-a]pyridine (50) as hinge binders led to 87% and 82% inhibition at 10 nM for CSF1R in the enzymatic assay, with IC50 values of 25 nM and 27 nM in MNFS60 cells, respectively. These derivatives significantly inhibited CSF1R phosphorylation in cells. Our approach could be utilized as a strategy to discover novel kinase inhibitors.

We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had comparable potency to 3 and were far more selective for ERRγ over the ERRα, -β, and ERα. The in vivo pharmacokinetic profiles of 6g and 10b were further evaluated, as they possessed superior in vitro ADMET profiles compared to the other compounds. Additionally, we observed a significant increase of fully glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in 6g- or 10b-treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, 6g and 10b possess advantageous druglike properties and can be used to potentially treat various ERRγ-related disorders.

BackgroundPrevious studies have identified risk factors for femoral arterial thrombosis after paediatric cardiac catheterisation, but none of them have evaluated the clinical and economic significance of this complication at the population level. Therefore, we examined the national prevalence and economic impact of femoral arterial thrombosis after cardiac catheterisation in children.MethodsPatients⩽18 years of age who underwent cardiac catheterisation were identified in the 2003–2009 Kids’ Inpatient Database. Patients were stratified by age as follows: ResultsAmong the 11,497 paediatric cardiac catheterisations identified, 4558 catheterisations (39.6%) were performed in children ConclusionsFemoral arterial thrombosis is especially prevalent in children

The use of intensity-modulated radiation therapy (IMRT) in rectal cancer has steadily increased over traditional 3D conformal radiotherapy (3D-CRT) due to perceived benefit of delivering higher treatment doses while minimizing exposure to surrounding tissues. However, IMRT is technically challenging and costly, and its effects on rectal cancer outcomes remain unclear.Adults with clinical stage II and III rectal adenocarcinoma who underwent neoadjuvant chemoradiotherapy with 45-54 Gy of radiation and surgery were included from the 2006-2013 National Cancer Data Base. Patients were grouped based the modality of radiation received: IMRT or 3D-CRT. Multivariable regression modeling adjusting for demographic, clinical, and treatment characteristics was used to examine the impact of IMRT vs. 3D-CRT on pathologic downstaging, resection margin positivity, sphincter loss surgery, 30-day unplanned readmission and mortality after surgery, and overall survival.Among 7386 patients included, 3330 (45 %) received IMRT and 4056 (55 %) received 3D-CRT. While the mean radiation dose delivered was higher with IMRT (4735 vs. 4608 cGy, p 0.001), it was associated with higher risks of positive margins (adjusted odds ratio (OR) 1.57; p 0.001) and sphincter loss surgery (OR 1.32; p 0.001). There were no differences between IMRT and 3D-CRT in the likelihood of pathologic downstaging (OR 0.89, p = 0.051), unplanned readmission (OR 0.79; p = 0.07), or 30-day mortality (OR 0.61; p = 0.31) after surgery. Additionally, there were no differences in overall survival at 8 years (IMRT vs. 3D-CRT: 64 vs. 64 %; adjusted hazard ratio 1.06, p = 0.47).IMRT is associated with worse local tumor control without any long-term survival benefit for patients with locally advanced rectal cancer. Given the lack of significant advantage and the higher cost of IMRT, caution should be exercised when using IMRT instead of traditional 3D-CRT for rectal cancer.

To examine the impact of alvimopan on outcomes and costs in a rigorous enhanced recovery colorectal surgery protocol.Postoperative ileus remains a major source of morbidity and costs in colorectal surgery. Alvimopan has been shown to reduce incidence of postoperative ileus in enhanced recovery colorectal surgery; however, data are equivocal regarding its benefit in reducing length of stay and costs.Patients undergoing major elective enhanced recovery colorectal surgery were identified from a prospectively-collected database (2010-2013). Multivariable analyses were employed to compare outcomes and hospital costs among patients who had alvimopan versus no alvimopan by adjusting for demographic, clinical, and treatment characteristics.A total of 660 patients were included; 197 patients received alvimopan and 463 patients had no alvimopan. In unadjusted analysis, the alvimopan group had a faster return of bowel function, shorter length of stay, and lower rates of ileus, Foley re-insertion, and urinary tract infection (all P 0.01). After adjustment, alvimopan was associated with a faster return of bowel function by 0.6 day (P = 0.0006), and lower incidence of postoperative ileus (odds ratio 0.23, P = 0.0002). With adjustment, alvimopan was associated with a shorter length of stay by 1.6 days (P = 0.002), and a hospital cost savings of $1492 per patient (P = 0.01).Alvimopan administration as an element of enhanced recovery colorectal surgery is associated with faster return of bowel function, lower incidence of postoperative ileus, shorter hospitalization, and a significant cost savings. These results suggest that alvimopan is cost-effective in the setting of enhanced recovery colorectal surgery protocols, and should therefore be considered in these programs.

Background/Purpose Sentinel lymph node biopsy (SLNB)-based management has been shown to improve disease-free survival in adult melanoma, but there is scant evidence regarding the utility of SLNB in pediatric melanoma. Methods The 2004–2011 Surveillance, Epidemiology, and End Results database was queried for patients with primary cutaneous melanoma of Breslow depth>0.75mm and clinically negative nodes. Pediatric patients, defined as less than 20years of age, were grouped by whether they underwent SLNB or not. Kaplan–Meier analysis was performed to compare melanoma-specific survival (MSS) in propensity-matched groups. Results 310 pediatric patients met study criteria: 261 (84%) underwent SLNB, while 49 (16%) did not. There was no difference in MSS between matched children who received SLNB and those who did not (p=0.36). Among children who received SLNB, a positive SLNB was associated with worse MSS compared to a negative SLNB (89% vs. 100% at 84months, p=0.04). However, children with a positive SLNB had more favorable survival compared to patients >20years of age (88% vs. 66% at 84months, p=0.02). Conclusions SLNB does not confer a survival benefit to children with melanoma, but it provides valuable prognostic information regarding MSS.

To examine survival of patients who underwent minimally invasive versus open low anterior resection (LAR) for rectal cancer.Utilization of laparoscopic and robotic LAR for rectal cancer has steadily increased. Short-term outcomes between these techniques and open surgery have shown equivalent results; however, survival outcomes are unknown.Adults from the National Cancer Data Base undergoing LAR for rectal adenocarcinoma were identified. Patients were stratified by intent-to-treat into open (OLAR) or minimally invasive LAR (MI-LAR). Multivariable modeling was used to compare short-term outcomes and survival between MI-LAR and OLAR and between laparoscopic (LLAR) and robotic LAR (RLAR).Among 14,033 patients included, 57.8% underwent OLAR and 42.2% MI-LAR. After adjustment, MI-LAR was associated with shorter length of stay (P 0.001), but similar rates of positive margins, 30-day readmission, 30-day mortality, and use of adjuvant therapies (all P 0.05). At 36 months, there was no difference in adjusted risk of mortality between MI-LAR and OLAR (hazard ratio [HR] 0.88, P = 0.089). In a subgroup analysis of LLAR versus RLAR, there were no differences in lymph node harvest, margin positivity, length of stay, readmission rate, 30-day mortality, or overall survival after adjustment (all P 0.05).Minimally invasive LAR for rectal cancer is associated with similar overall survival with the benefit of shorter hospitalization. Although the conversion rate is lower, robotic LAR is not associated with superior oncologic outcomes compared to laparoscopic LAR. Our findings support the ongoing adoption of minimally invasive techniques for rectal adenocarcinoma.

Several reports suggest that the efficacy of adjuvant chemotherapy on survival diminishes over time for colon cancer; however, precise timing of its loss of benefit has not been established.This study aimed to determine the relationship between time to adjuvant chemotherapy and survival and to identify a threshold for increased risk of mortality.This was a retrospective study. Multivariable Cox proportional hazard modeling with restricted cubic splines was used to evaluate the adjusted association between time to adjuvant chemotherapy and overall survival and to establish an optimal threshold for the initiation of therapy.Data were collected from the National Cancer Data Base.Adults who received adjuvant chemotherapy following resection of stage II to III colon cancers were selected.The primary outcome measured was overall survival.A total of 7794 patients were included. After adjusting for clinical, tumor, and treatment characteristics, our model determined a critical threshold of chemotherapy initiation at 44 days from surgery, after which there was an increase in the overall mortality. At a median follow-up of 61 months, the risk of mortality was increased in those who received adjuvant chemotherapy after 44 days from surgery (adjusted HR, 1.14; 95% CI, 1.05-1.24; p = 0.002), but not in those who received chemotherapy before 44 days from surgery (p = 0.11). Each additional week of delay was associated with a 7% decrease in survival (HR, 1.07; 95% CI, 1.04-1.10; p0.001).This study was limited by selection bias and the inability to compare specific chemotherapy regimens.This study objectively determines the optimal timing of adjuvant chemotherapy for patients with resected colon cancer. Delay beyond 6 weeks is associated with compromised survival. These findings emphasize the importance of the timely initiation of therapy, and suggest that efforts to enhance recovery following surgery have the potential to improve survival by decreasing delay to adjuvant chemotherapy.

Purpose Adrenocortical carcinoma (ACC) is a rare tumor in children with important distinctions from the adult disease. We reviewed the National Cancer Data Base (NCDB) to determine factors associated with long-term survival. Methods The NCDB was queried for patients less than 18years of age who were diagnosed with ACC between 1998 and 2011. Kaplan–Meier analysis was utilized to determine factors significantly associated with overall survival. Results A total of 111 patients were included (median age: 4years, 69% female). ACC was more common in the youngest cohort, with 48% of cases occurring in children younger than the age of 3. Median tumor size was 9.5cm (IQR: 6.5–13.0), and 87% of patients underwent some form of surgical resection. Among children with available data, 19 of 62 presented with metastases. Overall 1- and 3-year survival was 70% and 64%, respectively. Age, tumor size, extension of tumor into surrounding tissue, and metastatic disease were all found to be significantly associated with survival. Among patients who underwent a surgical procedure, margin status was also found to be significantly associated with survival. Conclusion Age, tumor size, extension of tumor, metastatic disease, and margin status are significantly associated with long-term survival in children with adrenocortical carcinoma.

Estrogen-related receptor gamma (ERRγ) is the NR3B subgroup of associated transcription factors. In this report, a new generation of a potent and selective ERRγ inverse agonist (25) with good biocompatibility was proposed. We also explored the potential of the newly developed compound 25 in the PDTC model to expand the original indications from ATC. In addition, an X-ray crystallographic study of the ligand and ERRγ co-complex showed that 25 completely binds to the target protein (PDB 6KNR ). Its medicinal chemistry, including a distinctive structural study to in vivo results, denotes that 25 may be directed towards the development of a pivotal treatment for ERRγ-related cancers.

Purpose: New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy–refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRγ) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC50 = 0.006 μmol/L), selective, and orally available ERRγ inverse agonist for NIS enhancement in ATC. Experimental Design: We sought to identify better ERRγ-targeting ligands and explored the crystal structure of ERRγ in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression, as well as radioiodine avidity was examined. ATC tumor–bearing mice were orally administered with DN200434, followed by 124I-positron emission tomography/CT (PET/CT). For radioiodine therapy, ATC tumor–bearing mice treated with DN200434 were administered 131I (beta ray–emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histologic analysis was performed to evaluate ERRγ expression status in normal tissue and ATC tissue, respectively. Results: DN200434–ERRγ complex crystallographic studies revealed that DN200434 binds to key ERRγ binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by 124I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histologic findings of patients with ATC showed higher ERRγ expression in tumors than in normal tissue, supporting ERRγ as a therapeutic target for ATC. Conclusions: DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.

OBJECTIVES To examine the effect of implementing postcatheterization ultrasound (US) on femoral arterial thrombosis detection rates and factors associated with thrombosis in infants. BACKGROUND Although femoral arterial thrombosis is an uncommon complication of cardiac catheterization, it can cause limb threatening complications. Previous studies assessing the utility of postprocedure US to detect thrombosis in infants have utilized US as an adjunct to standard clinical detection methods, are small scale, or include small cohorts of infants within older populations. METHODS We reviewed institutional records of patients 0-12 months undergoing catheterization from 2007 to 2016. Demographics and procedural data were compared between the thrombosis and non-thrombosis group. Pre- and post-US groups were compared for detected thrombosis rate. Using univariate and multivariable analyses, we identified factors associated with thrombosis. RESULTS In total, 270 patients underwent 509 catheterizations, with 40 (7.9%) documented thromboses. The rate of thrombus detection in patients younger than 6 months increased from 8.3% to 23.4% (P = 0.006) after implementing routine US. On multivariable analysis, lower weight (P

Blunt cerebrovascular injury (BCVI) is a rare consequence of blunt trauma. There appears to be benefit to an aggressive approach to screening for BCVI due to catastrophic sequelae of unrecognized injury. However, screening for BCVI carries extensive cost and oncologic risk to young patients. Foundational BCVI studies examined adults primarily, leaving question to the effectiveness of these criteria in children. We sought to evaluate BCVI screening criteria developed in primarily adult populations using a nationally representative pediatric dataset.We queried the 2008-2014 National Trauma Data Bank for patients with BCVI. Patients were stratified by age (adults18yrs, pediatric≤18yrs). Screening factors from the Modified Denver Criteria and Modified Memphis Criteria (GCS≤8, C1C3 cervical fracture, cervical subluxation, seatbelt sign, basilar skull fracture, mid-facial fracture, mandibular fracture, significant blood loss, coma, stroke, and hanging) were examined using univariate analysis and backwards-stepwise logistic regression to verify predictors of BCVI.Blunt injury occurred in 2,174,244 adults and 422,181 children; 5970 adults and 809 children sustained BCVI. In univariate analysis, all screening factors correlated with BCVI in both groups (p 0.001). When comparing BCVI patients, children more commonly experienced GCS≤8, seatbelt sign, basilar skull fracture, mid-facial fracture, mandibular fracture, and coma (p 0.05). In multivariable analysis, seatbelt sign was not associated with pediatric BCVI.Many adult-associated BCVI risk factors apply to children. Although children more commonly experience seatbelt sign, it does not independently cause increased BCVI risk. Given the rarity of pediatric BCVI, prospective multi-institutional studies are warranted to establish screening criteria specific to children.

Loos, Ruth J F/0000-0002-8532-5087; Sund, Reijo/0000-0002-6268-8117; Busjahn, Andreas/0000-0001-9650-6919; Tan, Qihua/0000-0003-3194-0030; Aliev, Fazil/0000-0001-8357-4699; Kaprio, Jaakko/0000-0002-3716-2455; Magnusson, Patrik/0000-0002-7315-7899; Tan, Qihua/0000-0003-3194-0030; ONCEL, Sevgi YURT/0000-0002-0990-292X; Ordonana, Juan R./0000-0001-7779-6017; Colodro-Conde, Lucia/0000-0002-9004-364X; Huibregtse, Brooke M./0000-0003-0977-7249; ROMERA, JUAN FRANCISCO SANCHEZ/0000-0002-5405-6216; Rebato, Esther/0000-0003-1221-8501; Pedersen, Nancy/0000-0001-8057-3543; Latvala, Antti/0000-0001-5695-117X; Silventoinen, Karri/0000-0003-1759-3079; Rasmussen, Finn/0000-0001-7915-7809; Piirtola, Maarit/0000-0001-7270-6676 WOS: 000438457400025 PubMed: 30001359 Background Smokers tend to weigh less than never smokers, while successful quitting leads to an increase in body weight. Because smokers and non-smokers may differ in genetic and environmental family background, we analysed data from twin pairs in which the co-twins differed by their smoking behaviour to evaluate if the association between smoking and body mass index (BMI) remains after controlling for family background. Methods and findings The international CODATwins database includes information on smoking and BMI measured between 1960 and 2012 from 156,593 twin individuals 18-69 years of age. Individual-based data (230,378 measurements) and data of smoking discordant twin pairs (altogether 30,014 pairwise measurements, 36% from monozygotic [MZ] pairs) were analysed with linear fixed-effects regression models by 10-year periods. In MZ pairs, the smoking co-twin had, on average, 0.57 kg/m(2) lower BMI in men (95% confidence interval (CI): 0.49, 0.70) and 0.65 kg/m(2) lower BMI in women (95% CI: 0.52, 0.79) than the never smoking co-twin. Former smokers had 0.70 kg/m(2) higher BMI among men (95% CI: 0.63, 0.78) and 0.62 kg/m(2) higher BMI among women (95% CI: 0.51, 0.73) than their currently smoking MZ cotwins. Little difference in BMI was observed when comparing former smoking co-twins with their never smoking MZ co-twins (0.13 kg/m(2), 95% CI 0.04, 0.23 among men; -0.04 kg/m(2), 95% CI -0.16, 0.09 among women). The associations were similar within dizygotic pairs and when analysing twins as individuals. The observed series of cross-sectional associations were independent of sex, age, and measurement decade. Conclusions Smoking is associated with lower BMI and smoking cessation with higher BMI. However, the net effect of smoking and subsequent cessation on weight development appears to be minimal, i.e. never more than an average of 0.7 kg/m(2). Academy of FinlandAcademy of Finland [266592, 100499, 205585, 118555, 141054, 265240, 263278, 264146]; Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium); ENGAGE - European Network for Genetic and Genomic Epidemiology [FP7- HEALTH-F4-2007, 201413]; National Institute of Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA-12502, AA-00145, AA-09203]; Academy of Finland Center of Excellence in Complex Disease GeneticsAcademy of Finland [213506, 129680]; Sigrid Juselius FoundationSigrid Juselius Foundation; Osaka University's International Joint Research Promotion Program; Medexpert Ltd., Budapest, Hungary; European Union's Seventh Framework Programmes ENGAGE ConsortiumEuropean Union (EU) [HEALTH-F4- 2007-201413]; BioSHaRE EU [HEALTH-F4-2010-261433]; Fundacion Seneca, Regional Agency for Science and Technology, Murcia, Spain [08633/PHCS/08, 15302/PHCS/10, 19479/PI/14]; Ministry of Science and Innovation, SpainSpanish Government [PSI2009-11560, PSI2014-56680-R]; Centre of Research Excellence grant from the National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [1079102]; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia; Australian Research CouncilAustralian Research Council; Australian National Health and Medical Research Council fellowshipNational Health and Medical Research Council of Australia [SRFB-1103623]; National Institutes of Health grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R21 AG039572]; National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIA R01 AG018384, R01 AG018386, R01 AG022381, R01 AG022982]; Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs; NIDAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [DA011015]; Longitudinal Twin Study [HD10333]; JSPS KAKENHI JP [23593419, 24792601, 26671010, 24590695, 26293128, 16K15385, 16K15978, 16K15989, 16H03261]; Global Research Network Program of the National Research Foundation [NRF 2011-220- E00006]; Kirikkale University Research Grant: KKUKirikkale University [2009/43]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114C117]; [5T32DA017637]; [5T32AG052371] This study was conducted within the CODATwins project (Academy of Finland grant #266592 to KS). Since its origin, the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7- HEALTH-F4-2007 (grant agreement number 201413), National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to RJ Rose), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to JK). JK also acknowledges support from the Sigrid Juselius Foundation. KS is supported by Osaka University's International Joint Research Promotion Program. Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. Data collection and research stemming from the Norwegian Twin Registry is supported, in part, from the European Union's Seventh Framework Programmes ENGAGE Consortium (grant agreement HEALTH-F4- 2007-201413), and BioSHaRE EU (grant agreement HEALTH-F4-2010-261433). The Murcia Twin Registry is supported by Fundacion Seneca, Regional Agency for Science and Technology, Murcia, Spain (08633/PHCS/08, 15302/PHCS/10 & 19479/PI/14) and Ministry of Science and Innovation, Spain (PSI2009-11560 & PSI2014-56680-R). The Australian Twin Registry is supported by a Centre of Research Excellence grant (ID 1079102) from the National Health and Medical Research Council administered by the University of Melbourne. The QIMR twin study acknowledges grants from the Australian National Health and Medical Research Council and the Australian Research Council. SM is supported by an Australian National Health and Medical Research Council fellowship (SRFB-1103623). The NAS-NRC Twin Registry acknowledges financial support from the National Institutes of Health grant number R21 AG039572. The Vietnam Era Twin Study of Aging was supported by National Institute of Health grants NIA R01 AG018384, R01 AG018386, R01 AG022381, and R01 AG022982, and, in part, with resources from the VA San Diego Center of Excellence for Stress and Mental Health. The Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA/NIH, or the VA. The Colorado Twin Registry is funded by NIDA-funded center grant DA011015 and Longitudinal Twin Study HD10333; BH was supported by 5T32DA017637 and 5T32AG052371. The Osaka University Aged Twin Registry is supported by grants from JSPS KAKENHI JP (23593419, 24792601, 26671010, 24590695, 26293128, 16K15385, 16K15978, 16K15989, 16H03261). The Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011-220- E00006). SO and FA are supported by Kirikkale University Research Grant: KKU, 2009/43 and TUBITAK grant 114C117.; None of the funders including HealthTwiSt GmbH and Pfizer Inc played a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries, excluding HealthTwiSt GmbH and Pfizer Inc, and/or research materials. The funder HealthTwiSt GmbH did not provide support in the form of salaries for authors (AB). HealthTwiSt GmbH collects data on twin samples and makes these available to academic researchers for a service fee to cover the costs (technical staff salaries and material costs). The funder (Pfizer Inc) did provide support in the form of consultation fees for authors (JK and TK) outside of the submitted work.

Purpose Internal mammary lymph node (IMN) involvement is associated with poor prognosis in breast cancer. This study investigated the treatment outcomes of initial clinically IMN-positive breast cancer patients who received adjuvant radiotherapy (RT), including IMN irradiation, following primary breast surgery. Materials and Methods We retrospectively reviewed data of 95 breast cancer patients with clinically detected IMNs at diagnosis treated with surgery and RT between June 2009 and December 2015. Patients received adjuvant RT to the whole breast/chest wall and regional lymph node (axillary, internal mammary, and supraclavicular) areas. Twelve patients received an additional boost to the IMN area. Results The median follow-up was 43.2 months (range, 4.5 to 100.5 months). Among 77 patients who received neoadjuvant chemotherapy, 52 (67.5%) showed IMN normalization and 19 (24.6%) showed a partial response to IMN. There were 3 and 24 cases of IMN failure and any recurrence, respectively. The 5-year IMN failure-free survival, disease-free survival (DFS), and overall survival (OS) were 96%, 70%, and 84%, respectively. IMN failure-free survival was significantly affected by resection margin status (97.7% if negative, 87.5% for close or positive margins; p = 0.009). All three patients with IMN failure had initial IMN size ≥1 cm and did not receive IMN boost irradiation. The median age of the three patients was 31 years, and all had hormone receptor-negative tumors. Conclusion RT provides excellent IMN control without the support of IMN surgery. Intensity-modulated radiotherapy, including IMN boost for breast cancer patients, is a safe and effective technique for regional lymph node irradiation.

Hair loss is a major dermatological disease in veterinary and human medicine. Active studies on hair regeneration with mesenchymal stem cells have been performed in an effort to solve the limitations of conservative treatments in human medicine. Our understanding of the canine hair follicle (HF), considering a useful model for the study of the human alopecia, is limited. This study was designed to broaden our understanding of canine dermal papilla (DP), and to reconstruct dermal papilla-like tissue (DPLT) using canine adipose-derived mesenchymal stem cells (AD-MSCs), as an alternative to actual DP. We cultured canine DPs, observed their culture patterns and compared their expression level of DP-related genes and proteins with those of DPLTs by performing RT-PCR analysis and Western blotting. Canine dermal papilla cells (DPCs) showed multilayer culture patterns with pseudo-papillae. Reconstruction of DPLTs was performed successfully. Not only were they morphologically similar to actual DPs, but we also observed similarities between DPCs and DPLTs in molecular characteristics. These findings suggested that DPLT was a viable substitute for DP. This study will not only be helpful for understanding the morphological and molecular characteristics of canine DPCs, but may also serve as a basis for understanding human hair follicle biology and potential therapeutic strategies for alopecia.

Background We investigated baseline anthropometric/metabolic traits predicting incident diabetes, genetic/environmental relationships between these traits and HbA1c at follow-up and the contribution of genetics, covariates and environments to variance in HbA1c at follow-up and incident diabetes. Methods Nondiabetic twins (n = 869) and their family members (n = 949) were followed over 3.7 ± 1.4 years (44.3 ± 12.8 years of age); baseline anthropometric/metabolic traits were measured. Fasting plasma glucose and HbA1c were measured at follow-up. Incident diabetes was defined as HbA1c ≥6.5% or fasting plasma glucose ≥7 mmol/L. Results Age-adjusted incident diabetes was 4.9% in men and 4.1% in women. Odd ratio for incident diabetes was 2.34–2.40, 1.25-1.28, 1.22–1.27 and 1.89 per standard deviation of baseline fasting plasma glucose, white blood cell (WBC), triglycerides and waist circumference, respectively, in multivariate generalized estimating equation models (p

Practice guidelines differ in their support of adjuvant chemotherapy use in patients who received preoperative chemoradiation for rectal cancer.The purpose of this study was to evaluate the impact of adjuvant chemotherapy among patients with locally advanced rectal cancer who received neoadjuvant chemoradiation and surgery.This was a retrospective study. Multivariable Cox proportional hazard modeling was used to evaluate the adjusted survival differences.Data were collected from the National Cancer Database.Adults with pathologic stage II and III rectal adenocarcinoma who received neoadjuvant chemoradiation and surgery were included.Overall survival was measured.Among 12,696 patients included, 4023 (32%) received adjuvant chemotherapy. The use of adjuvant chemotherapy increased over the study period from 23% to 36%. Although older age and black race were associated with a lower likelihood of receiving adjuvant chemotherapy, patients with higher education level and stage III disease were more likely to receive adjuvant chemotherapy (all p0.05). At 7 years, overall survival was improved among patients who received adjuvant chemotherapy (60% vs. 55%; p0.001). After risk adjustment, the use of adjuvant chemotherapy was associated with improved survival (HR = 0.81 (95% CI, 0.72-0.91); p0.001). In the subgroup of patients with stage II disease, survival was also improved among patients who received adjuvant chemotherapy (68% vs 58% at 7 y; p0.001; HR = 0.70 (95% CI, 0.57-0.87); p = 0.002). Among patients with stage III disease, the use of adjuvant chemotherapy was associated with a smaller but persistent survival benefit (56% vs 51% at 7 y; p = 0.017; HR = 0.85 (95% CI, 0.74-0.98); p = 0.026).The study was limited by its potential for selection bias and inability to compare specific chemotherapy regimens.The use of adjuvant chemotherapy among patients with rectal cancer who received preoperative chemoradiation conferred a survival benefit. This study emphasizes the importance of adjuvant chemotherapy in the management of rectal cancer and advocates for its increased use in the setting of neoadjuvant therapy. See Video Abstract at http://link.lww.com/DCR/A428.

Foetus-in-fetu is a rare condition in which one ‘twin’ is found inside the other, with a prevalence of only one in 500,000 pregnancies. The embryo-pathogenesis is a manifestation of anomalous monoz...

Exacerbation of COPD is a major risk factor for bad prognosis of COPD. A few plasma proteins have been discovered to associate with hospital admission due to exacerbation up to date. We tried to find new plasma biomarkers to predict the exacerbation of COPD.We examined the plasma of normal control (n = 8) and COPD stable (n = 8) and exacerbation (n = 8) using 2-Dimentional Electrophoresis. The differentially expressed protein spots were identified by MALDI-TOF. ELISA were performed for quantitative measurement of RARα in plasma from normal control (n = 37) and COPD (n = 35).17 proteins were differentially expressed in plasma between stable and exacerbation state in the subjects with COPD. Identification using MALDI-TOF showed that retinoic acid receptor alpha, ninein, isoform CRA_a, alpha-1 antitrypsin, fibrinogen gamma, tyrosyl-DNA phosphodiesterase 2, and T cell receptor delta chain were increased in exacerbation of COPD, while fibrin beta, Crystal Structure Of An Autoimmune Complex Between A Human Igm RF* And Igg1 Fc, transferrin, serpin peptidase inhibitor member 6, complement factor B preproprotein, Chain B, Crig Bound To C3c, and WD repeat-containing protein 1 isoform 1 were decreased. Quantitative measurement showed that RARα plasma levels significantly increased in exacerbation state compared to stable state of COPD (n = 14). In the plasma of stable state, the COPD subjects (n = 14) having more than 0.4 time/yr of admission had very high levels of RAR alpha protein and those (n = 11) having less than 0.4 times/yr of admission had the intermediate levels compared to those having no exacerbation (n = 10). ROC analysis of RAR alpha levels to frequency of admission showed an area under the curve of 0.844. A cut-off of 0.154 ng/ml of RAR alpha predicted hospital admission with a sensitivity of 71.4% and a specificity of 92.8%.The proteomic analysis of plasma indicates that alteration of several proteins may be associated with admission of COPD. Among them, plasma RAR alpha level may predict hospital admission with a sensitivity of 71.4% and a specificity of 92.8%.

Purpose The role of helicopter emergency medical services (HEMS) in pediatric trauma remains controversial. We examined its use in pediatric trauma and its effectiveness in children with moderate/severe injuries. Methods All blunt/penetrating trauma patients ≤18years old in the National Trauma Data Bank were evaluated for use of HEMS and in-hospital mortality. In a comparative effectiveness study, only patients treated at level I/II pediatric centers with injury severity score (ISS)≥9 were included. Results Of 127,489 included patients, 18,291 (14%) arrived via HEMS, compared to 56% by ground ambulance and 29% by private vehicle/walk-in. HEMS patients had more severe injuries (ISS≥25; 28% vs. 14%) and altered mental status (GCS≤8; 29% vs. 11%), but also contained many patients with only minor injuries or no major physiologic derangements. In unadjusted analysis, HEMS was associated with increased mortality (OR: 1.6; 95% CI: 1.4–1.7). However, it had decreased mortality by regression (0.5; 0.4–0.6) and propensity analysis (0.7; 0.6–0.8) to adjust for confounders. Conclusion We found multiple indicators for overuse of HEMS, with nearly 40% of children having only minor injuries. In moderate/severe injuries, HEMS is associated with decreased mortality, potentially saving one life for every 47 flights. Research is needed to determine appropriate criteria for helicopter triage. Comparative Study/Level of evidence III

Background Renal medullary carcinoma (RMC) is an aggressive malignancy seen predominantly in young males with sickle cell trait. RMC is poorly understood, with fewer than 220 cases described in the medical literature to date. We used a large national registry to define the typical presentation, treatments, and outcomes of this rare tumor. Methods The National Cancer Database was queried for patients under 40 years of age diagnosed with RMC from 1998 to 2011. An analysis of patient and tumor characteristics, treatment details, and overall survival (OS) was undertaken, and factors associated with mortality were identified using multivariable regression analysis. Results In total, 159 patients with RMC were identified, of whom a majority were male (71%), African American (87%), and had metastatic disease (71%). Median tumor size was 6 cm and median survival was 7.7 months. Most patients underwent surgery (60%) and chemotherapy (65%). Few patients received radiation (12%). Patients with metastatic disease had a significantly worse median survival (4.7 vs. 17.8 months, P < 0.001) and were less likely to receive surgery (42% vs. 91%, P < 0.001). Age and tumor size did not appear to impact OS. Conclusion In the largest cohort to date of patients with RMC, we found a dismal median survival of less than 8 months. Age and tumor size were not associated with OS. Metastatic disease at presentation was the main negative prognostic indicator in RMC and was present in a majority of patients at the time of diagnosis.

Hand-assisted laparoscopic surgery (HALS) is often used in procedures too complex for completely minimally invasive approaches. However, there are concerns for whether this hybrid approach abrogates perioperative benefits of the completely minimally invasive technique. We queried the 2012–2013 National Surgery Quality Improvement Program for adults undergoing elective HALS or open colectomy (OC). After propensity matching, short-term outcomes were compared. Subset analysis was performed for segmental resections. Multivariate analysis was used to determine predictors of utilizing either approach. This query included 8791 patients (OC 2707, HALS 6084). Predictors of HALS included male sex (OR 1.17, p = 0.006), increasing BMI (OR 1.01, p = 0.02), benign indication (OR 1.48, p