Search

Supplementary Figures 1-4 from ID1 Enhances Docetaxel Cytotoxicity in Prostate Cancer Cells through Inhibition of p21

Supplementary Figure Legends 1-12 from ID1 Enhances Docetaxel Cytotoxicity in Prostate Cancer Cells through Inhibition of p21

Supplementary Figures 7-9 from ID1 Enhances Docetaxel Cytotoxicity in Prostate Cancer Cells through Inhibition of p21

Supplementary Figure 12 from ID1 Enhances Docetaxel Cytotoxicity in Prostate Cancer Cells through Inhibition of p21

Supplementary Figures 5-6 from ID1 Enhances Docetaxel Cytotoxicity in Prostate Cancer Cells through Inhibition of p21

Introduction The purpose of this study was to develop a multi-institutional registry to characterize the demographics, management, and outcomes of a contemporary cohort of children undergoing congenital lung malformation (CLM) resection. Methods After central reliance IRB approval, a web-based, secure database was created to capture retrospective cohort data on pathologically-confirmed CLMs performed between 2009 and 2015 within a multi-institutional research collaborative. Results Eleven children's hospitals contributed 506 patients. Among 344 prenatally diagnosed lesions, the congenital pulmonary airway malformation volume ratio was measured in 49.1%, and fetal MRI was performed in 34.3%. One hundred thirty-four (26.7%) children had respiratory symptoms at birth. Fifty-eight (11.6%) underwent neonatal resection, 322 (64.1%) had surgery at 1–12 months, and 122 (24.3%) had operations after 12 months. The median age at resection was 6.7 months (interquartile range, 3.6–11.4). Among 230 elective lobectomies performed in asymptomatic patients, thoracoscopy was successfully utilized in 102 (44.3%), but there was substantial variation across centers. The most common lesions were congenital pulmonary airway malformation (n = 234, 47.3%) and intralobar bronchopulmonary sequestration (n = 106, 21.4%). Conclusion This multicenter cohort study on operative CLMs highlights marked disease heterogeneity and substantial practice variation in preoperative evaluation and operative management. Future registry studies are planned to help establish evidence-based guidelines to optimize the care of these patients. Level of evidence Level II.

Human papillomavirus (HPV) infection is the major risk factor for anal dysplasia that may progress to squamous cell carcinoma of the anus. We have previously shown that systemic administration of a PI3K/mTOR inhibitor (BEZ235), an autophagic inducer, results in decreased squamous cell carcinoma of the anus in our HPV mouse model. In this study, we investigate the effect of the local, topical application of a BEZ235 on tumor-free survival, histopathology, PI3K/mTOR, and autophagy. The rationale for investigating a topical formulation is the localized nature of anal dysplasia/cancer and the goal for creating a clinically translatable formulation to decrease anal carcinogenesis. In this study, HPV transgenic mice were given no treatment, topical BEZ235, topical 7,12 dimethylbenz[a]anthracene (DMBA) (carcinogen), or both topical DMBA + BEZ235. Mice were assessed for tumor development and treatment-related toxicities. Tissue was evaluated for histology, PI3K/mTOR inhibition (pS6 and pAkt), and autophagy (LC3β and p62). DMBA-alone mice had an average of 16.9 weeks tumor-free survival, whereas mice receiving both DMBA+topical BEZ235 had 19.3 weeks (P < 0.000001). Histopathology revealed a significant decrease in dysplasia/carcinoma with the addition of topical BEZ235 to DMBA (P < 0.000001). Comparing DMBA versus DMBA + BEZ235, topical BEZ235 resulted in a significant decrease in both pS6 and pAkt (P < 0.001). Compared with no-treatment mice, both BEZ235-treated and DMBA + BEZ235-treated mice had significantly higher LC3β expression, signifying autophagic induction (P < 0.01), whereas DMBA-treated, BEZ235-treated, and DMBA+BEZ235-treated mice had a significantly lower p62 expression, signifying active autophagy (P < 0.0005). In conclusion, consistent with systemic delivery, topical application of BEZ235 shows decreased anal carcinogenesis through the activation of autophagy.

Objective Endovascular aneurysm repair (EVAR) is a widely used option for patients with suitable vascular anatomy who have a large infrarenal abdominal aortic aneurysm (AAA). Patients with small AAAs are managed with careful surveillance and it is a common concern that their anatomy may change with AAA growth, and their option for EVAR may become limited. Device innovation has resulted in expanded ranges of anatomy that may be eligible for EVAR. This study sought to identify changes in anatomic eligibility for repair with contemporary endovascular devices in AAA patients, monitored by computed tomography scan over the course of 2 years. Methods Patients from the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT, NCT01756833) were included in this analysis. Females had baseline AAA maximum transverse diameter between 3.5 and 4.5 cm, and males had baseline maximum transverse diameter between 3.5 and 5.0 cm. Patients were included in this analysis if they completed pre-enrollment and 2-year follow-up computed tomography imaging. Pertinent anatomic measurements were performed on a postprocessing workstation in a centralized imaging core laboratory. EVAR candidacy was determined by measuring proximal aortic neck diameter, AAA length, and infrarenal neck angulation. Patients were considered to be eligible for EVAR if they qualified for at least one of the seven studied devicesʼ instructions for use at baseline and at 2 years. A paired t test analysis was used to detect differences in aortic measurements over 2 years, and the McNemar test was used to compare eligibility over 2 years. Results We included 192 patients in this analysis—168 male and 24 female. Of these patients, 85% were eligible for EVAR at baseline and 85% after 2 years of follow-up (P = 1.00; 95% confidence interval –0.034 to 0.034). Of the 164 EVAR candidates at baseline, 160 (98%) remained eligible over 2 years of surveillance. Insufficient neck length was the most common reason for both ineligibility at baseline (18 of 28 patients) as well as loss of candidacy over 2 years (3 of 4 patients). Conclusions The majority of patients eligible for EVAR when entering a surveillance program for small AAA remain eligible after 2 years. Substantial changes in AAA neck anatomy resulting in loss of EVAR treatment options are infrequent. Patients with anatomic AAA progression beyond EVAR eligibility remain candidates for complex EVAR and open repair.

Low-grade anal dysplasia is a disease that can progress to high-grade anal dysplasia and eventually anal cancer if left untreated. Research has shown that low-grade anal dysplasia is marked by significant autophagic dysfunction. We hypothesized that systemic induction of autophagy, via phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibition, would be effective in preventing anal cancer development in human papillomavirus (HPV) mice (K14E6/E7) with established low-grade anal dysplasia. Mice began treatment at 15 weeks of age, when 75% of mice spontaneously develop low-grade anal dysplasia, and were divided into the following groups: no treatment, systemic LY3023414 (4.5 mg/kg, dual PI3K/mTOR inhibitor) alone, topical 7,12 dimethylbenz[a]anthracene (DMBA) alone, or systemic LY3023414 and topical DMBA. Groups were compared for final histology, PI3K activity, mTOR activity, autophagic induction (light chain 3B (LC3β)), autophagic function (p62 protein), and tumor-free survival. Untreated mice or mice treated with LY3023414 alone did not progress to cancer. There was a statistically significant decrease in the number of mice that developed histologic evidence of cancer when comparing mice that received systemic LY3203414 with topical DMBA versus those that received topical DMBA alone (p = 0.0003). PI3K and mTOR activity decreased in groups treated with systemic LY3023414 and topical DMBA as compared with those treated with topical DMBA alone (p = 0.0005 and p = 0.0271, respectively). LC3β and p62 expression was not statistically altered with systemic LY3023414 treatment. Mice developed less overt tumors and had increased tumor-free survival when treated with systemic LY3023414 in the presence of topical DMBA compared to topical DMBA alone (p = 0.0016 and p 0.001, respectively). Systemic LY3023414 treatment is effective in anal cancer prevention in the setting of established low-grade anal dysplasia in an HPV-associated mouse model of anal cancer.

Background: This study compares the morphology and outcomes of acute retrograde type A dissections (RTADs) with acute antegrade type A dissections (ATADs), and acute type B dissections. Materials and methods: From 2000 to 2016, there were 12 acute RTADs, 96 ATADs, and 92 type B dissections with available imaging. Dissections were characterized using computerized tomography angiography images. We examined clinical features, tear characteristics, and various morphologic measurements. Results: Compared with acute type B dissections, RTAD primary tears were more common in the distal arch (75% versus 43%, P = 0.04), and the false-to-true lumen contrast intensity ratio at the mid-descending thoracic aorta was lower (0.46 versus 0.71, P = 0.020). RTAD had less false lumen decompression because there were fewer aortic branch vessels distal to the subclavian that were perfused through the false lumen (0.40 versus 2.19, P < 0.001). Compared with ATAD, RTAD had less root involvement where root true-to-total lumen area ratio was higher (0.88 versus 0.76, P = 0.081). Furthermore, RTAD had a lower false-to-true lumen contrast intensity ratio at the root (0.25 versus 0.57, P < 0.05), ascending aorta (0.25 versus 0.72, P < 0.001), and proximal arch (0.39 versus 0.67, P < 0.05). RTAD were more likely to undergo aortic valve resuspension (100% versus 74%, P = 0.044). Conclusions: RTAD tends to occur when primary tears occur in close proximity to the aortic arch and when false lumen decompression through the distal aortic branches are less effective. Compared with ATAD, RTAD has less root involvement, and successful aortic valve resuspension is more likely.

Purpose The purpose of this study was to determine the diagnostic accuracy of tumor markers for malignancy in girls with ovarian neoplasms. Methods A retrospective review of girls 2–21 years who presented for surgical management of an ovarian neoplasm across 10 children's hospitals between 2010 and 2016 was performed. Patients who had at least one concerning feature on imaging and had tumor marker testing were included in the study. Sensitivity, specificity, and negative and positive predictive values (PPV) of tumor markers were calculated. Results Our cohort included 401 patients; 22.4% had a malignancy. Testing for tumor markers was inconsistent. AFP had high specificity (98%) and low sensitivity (42%) with a PPV of 86%. The sensitivity, specificity, and PPV of beta-hCG was 44%, 76%, and 32%, respectively. LDH had high sensitivity (95%) and Inhibin A and Inhibin B had high specificity (97% and 92%, respectively). Conclusions Tumor marker testing is helpful in preoperative risk stratification of ovarian neoplasms for malignancy. Given the variety of potential tumor types, no single marker provides enough reliability, and therefore a panel of tumor marker testing is recommended if there is concern for malignancy. Prospective studies may help further elucidate the predictive value of tumor markers in a pediatric ovarian neoplasm population. Type of Study Retrospective Cohort Review. Level of Evidence Level III.

The purpose of this study was to evaluate the clinical presentation and operative outcomes of patients with congenital lobar emphysema (CLE) within a large multicenter research consortium.After central reliance IRB-approval, a retrospective cohort study was performed on all operatively managed lung malformations at eleven participating children's hospitals (2009-2015).Fifty-three (10.5%) children with pathology-confirmed CLE were identified among 506 lung malformations. A lung mass was detected prenatally in 13 (24.5%) compared to 331 (73.1%) in non-CLE cases (p 0.0001). Thirty-two (60.4%) CLE patients presented with respiratory symptoms at birth compared to 102 (22.7%) in non-CLE (p 0.0001). The most common locations for CLE were the left upper (n = 24, 45.3%), right middle (n = 16, 30.2%), and right upper (n = 10, 18.9%) lobes. Eighteen (34.0%) had resection as neonates, 30 (56.6%) had surgery at 1-12 months of age, and five (9.4%) had resections after 12 months. Six (11.3%) underwent thoracoscopic excision. Median hospital length of stay was 5.0 days (interquartile range, 4.0-13.0).Among lung malformations, CLE is associated with several unique features, including a low prenatal detection rate, a predilection for the upper/middle lobes, and infrequent utilization of thoracoscopy. Although respiratory distress at birth is common, CLE often presents clinically in a delayed and more insidious fashion.Level III.

Background: The dynamic role of autophagy in cancer development is a topic of considerable research and debate. Previously published studies have shown that anal cancer development can be promoted or prevented with the pharmacologic inhibition or induction, respectively, of autophagy in a human papillomavirus (HPV) mouse model. However, these results are confounded by the fact that the drugs utilized are known to affect other pathways besides autophagy. It has also been shown that autophagic inhibition occurs in the setting of HPV16 oncoprotein expression (E6 and E7) and correlates with increased susceptibility to anal carcinogenesis. Materials and Methods: In this study, we employed a conditional, genetic, autophagic (Atg7) knockout mouse model to determine conclusively that autophagy has a role in anal cancer development, in the absence or presence of E6 and E7. Results: In mice lacking both HPV16 oncogenes, knockout of autophagy followed by exposure to a carcinogen resulted in a tumor incidence of 40%, compared to 0% in mice treated with a carcinogen alone with an intact autophagic pathway (P = 0.007). In mice expressing either one or both HPV16 oncoproteins, the addition of genetic knockout of autophagy to carcinogen treatment did not lead to a significant difference in tumor incidence compared to carcinogen treatment alone, consistent with the ability of HPV oncogenes to inhibit autophagy in themselves. Conclusions: These results provide the first conclusive evidence for the distinct role of autophagy in anal carcinogenesis, and suggest that autophagy is a plausible target for therapies aimed at reducing anal dysplasia and anal cancer development.

OBJECTIVE: This study investigated the growth and behavior of the ascending aorta in patients with descending thoracic aortic disease. METHODS: We examined 200 patients with descending thoracic aortic disease including acute type B dissection (n = 95), chronic type B dissection (n = 38), intramural hematoma (n = 23), and thoracoabdominal aortic aneurysms (n = 44). Images from computed tomography and magnetic resonance imaging were evaluated after three-dimensional reconstruction to examine the growth rate in those with >1 year of imaging follow-up (n = 108). Survival data were derived from all 200 patients in this study. RESULTS: Average proximal aortic dimensions at the index image were relatively small, measuring 3.65 ± 0.51 cm in the root, 3.67 ± 0.48 cm in the ascending aorta, and 3.50 ± 0.44 cm in the proximal arch. Average growth rate was low for the aortic root, ascending aorta, and proximal arch at 0.36 ± 0.64 mm/y, 0.26 ± 0.44 mm/y, and 0.25 ± 0.44 mm/y, respectively. There was no difference in baseline proximal aortic dimensions and growth rate between the four subgroups. An index aortic diameter ≥4.1 cm grew faster than those

Background Whether primary tear size impacts extent of type A dissection is unclear. Using statistical groupings based on dissection morphology, we examined its relationship to primary tear area. Methods We retrospectively reviewed 108 patients who underwent acute ascending dissection repair from 2000-2016. Dissection morphology was characterized using 3-dimensional (3D) reconstructions of computed tomography (CT) scan images. Two-step cluster analysis was performed to group the dissections by examining the true lumen area as a fraction of the total aortic area at various levels. Results Cluster analysis defined two distinct categories. This first grouping corresponds to DeBakey type I (n=71, 65.7%) with a dissection extending from the ascending aorta to the aortic bifurcation. The second grouping conforms more closely to DeBakey type II dissection (n=37, 34.3%). It differs however from the classic type II definition as the dissection may extend up to the distal arch from the ascending aorta. Compared to type I, this "extended" DeBakey type II had no malperfusion (P

Autophagy is an intracellular, catabolic process that maintains cellular health. We examined the response of pharmacologic modulation of autophagy in an HPV mouse model of anal carcinogenesis. K14E6/E7 mice were treated with the topical carcinogen DMBA weekly and assessed for tumors over 20 weeks. Concurrently, they were given either chloroquine or BEZ235, to inhibit or induce autophagy, respectively. Time to tumor onset was examined. Immunofluorescence (IF) was performed for LC3β and p62 to examine autophagy. All DMBA treated K14E6/E7 mice developed anal cancer, contrary to zero of the no DMBA treated mice. Chloroquine plus DMBA resulted in a significant decrease in the time to tumor onset compared to K14E6/E7 treated with DMBA. Only 40% BEZ235 plus DMBA treated mice developed anal cancer. Autophagic induction with DMBA and BEZ235, and autophagic inhibition with chloroquine were confirmed via IF. Anal carcinogenesis can be inhibited or induced via pharmacologic modulation of autophagy.