281 results on '"Prinz RA"'
Search Results
2. Endoscopic ultrasound for diagnosis and staging of pancreatic tumors
- Author
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Harrison, JL, primary, Millikan, KW, additional, Prinz, RA, additional, and Zaidi, S, additional
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- 1998
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3. Heparanase-1 gene expression and regulation by high glucose in renal epithelial cells: a potential role in the pathogenesis of proteinuria in diabetic patients.
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Maxhimer JB, Somenek M, Rao G, Pesce CE, Baldwin D Jr., Gattuso P, Schwartz MM, Lewis EJ, Prinz RA, Xu X, Maxhimer, Justin B, Somenek, Michael, Rao, Geetha, Pesce, Catherine E, Baldwin, David Jr, Gattuso, Paolo, Schwartz, Melvin M, Lewis, Edmund J, Prinz, Richard A, and Xu, Xiulong
- Abstract
The molecular mechanisms of heparan sulfate proteoglycan downregulation in the glomerular basement membrane (GBM) of the kidneys with diabetic nephropathy remain controversial. In the present study, we showed that the expression of heparanase-1 (HPR1), a heparan sulfate-degrading endoglycosidase, was upregulated in the renal epithelial cells in the kidney with diabetic nephropathy. Urinary HPR1 levels were elevated in patients with diabetic nephropathy. In vitro cell culture studies revealed that HPR1 promoter-driven luciferase reporter gene expression, HPR1 mRNA, and protein were upregulated in renal epithelial cells under high glucose conditions. Induction of HPR1 expression by high glucose led to decreased cell surface heparan sulfate expression. HPR1 inhibitors were able to restore cell surface heparan sulfate expression. Functional analysis revealed that renal epithelial cells grown under high glucose conditions resulted in an increase of basement membrane permeability to albumin. Our studies suggest that loss of heparan sulfate in the GBM with diabetic nephropathy is attributable to accelerated heparan sulfate degradation by increased HPR1 expression. [ABSTRACT FROM AUTHOR]
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- 2005
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4. Recurrent occult medullary thyroid carcinoma detected by MR imaging
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Crow, JP, primary, Azar-Kia, B, additional, and Prinz, RA, additional
- Published
- 1989
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5. Insulin and Glucagon in Human Pancreatic Exocrine Fluid
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L. Kirsteins, A M Lawrence, E. B. Paloyan, E. Connick, and Prinz Ra
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medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,Biochemistry (medical) ,Clinical Biochemistry ,General Medicine ,Glucagon ,Biochemistry ,Endocrinology ,Intestinal Absorption ,Pancreatic Juice ,Internal medicine ,Pancreatic juice ,medicine ,Humans ,business ,Digestive System - Published
- 1980
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6. Validated predictive model for treatment and prognosis of adrenocortical carcinoma.
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Zuber SM, Kuchta K, Holoubek SA, Khokar A, Moo-Young T, Prinz RA, and Winchester DJ
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- Humans, Prognosis, Proportional Hazards Models, Adrenocortical Carcinoma therapy, Adrenal Cortex Neoplasms therapy
- Abstract
Background: Adrenocortical carcinoma has a poor prognosis and multiple clinical, pathological, and treatment variables. Currently, we lack a prognostic and treatment calculator to determine the survival and efficacy of adjuvant chemoradiation. We aimed to validate a calculator to assess prognosis and treatment., Methods: We searched the National Cancer Database to identify patients with adrenocortical carcinoma surgically treated from 2004 to 2020 and randomly allocated them into a training (80%) or validation set (20%). We analyzed the variables of age; sex; Charlson Comorbidity Index; insurance status; tumor size; pathologic tumor, node, and metastasis categories; surgical margins; and use of chemotherapy and radiation therapy. We used Cox regression prediction models and bootstrap coefficients to generate a mathematical model to predict 5- and 10-year overall survival. After using the area under the curve analysis to assess the model's performance, we compared overall survival in the training and validation sets., Results: Multivariable analysis of the 3,480 patients included in the study revealed that all variables were significant except sex (P < .05) and incorporated into a mathematical model. The area under the curve for 5- and 10-year overall survival was 0.68 and 0.70, respectively, for the training set and 0.70 and 0.72, respectively, for the validation set. For the bootstrap coefficients, the 5- and 10-year overall survival was 6.4% and 4.1%, respectively, above the observed mean., Conclusion: Our model predicts the overall survival of patients with adrenocortical carcinoma based on clinical, pathologic, and treatment variables and can assist in individualizing treatment., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2024
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7. Treatment Differences for Adrenocortical Carcinoma by Race and Insurance Status.
- Author
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Holoubek SA, MacKinney EC, Khokar AM, Kuchta KM, Winchester DJ, Prinz RA, and Moo-Young TA
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- Humans, United States epidemiology, Healthcare Disparities, Insurance Coverage, Medically Uninsured, Adrenocortical Carcinoma surgery, Adrenal Cortex Neoplasms surgery
- Abstract
Introduction: To determine if treatment and clinical outcomes of adrenocortical carcinoma (ACC) vary by race and insurance status., Methods: ACC patients from the National Cancer Database (2004-2017) were reviewed. Race was defined as White versus minority (Black and Hispanic). Insurance types were private (PI) versus other (Medicaid/uninsured/unknown). Metastatic ACC (M-ACC) was defined as distant metastases at the time of diagnosis; nonmetastatic ACC (NM-ACC) patient had no distant disease., Results: Of 2351 NM-ACC patients, 83.6% were White and 16.4% minority. There were 1216 M-ACC patients, with 80.3% White and 19.8% minority. Both White NM-ACC and M-ACC patients had more PI (each P < 0.001). PI NM-ACC was associated with a shorter duration from diagnosis to first treatment (14 versus 18 d, P = 0.005). Both NM-ACC and M-ACC with PI were more likely to receive surgery (92.6% versus 86.9%, P = 0.001 and 35.4% versus 27%, P = 0.02) and to receive surgery sooner (13 versus 16 d, P = 0.03). M-ACC with PI were more likely to receive chemotherapy (63.6% versus 54.3%, P = 0.01) and to have lymph nodes examined (14.8% versus 8.6%, P = 0.02). Length of stay postoperatively was shorter for White NM-ACC (6 versus 7 d, P = 0.04) and M-ACC (8 versus 17 d, P = 0.02). For NM-ACC and M-ACC, the 30-d readmission, 90-d mortality, and overall survival were similar by race. A multivariable analysis showed minorities (OR 0.69, 95% confidence interval 0.54-0.88, P = 0.003) and patients without PI (OR 0.75, 95% confidence interval 0.58-0.97, P = 0.03) were less likely to have surgery. However, a multivariable analysis showed survival was similar for White versus minority patients and PI versus other., Conclusions: White NM-ACC or M-ACC and PI were more likely to receive surgery and timely multimodality care. These disparities were not associated with differences in 90-d mortality or overall survival., (Copyright © 2022. Published by Elsevier Inc.)
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- 2022
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8. H5N1 infection impairs the alveolar epithelial barrier through intercellular junction proteins via Itch-mediated proteasomal degradation.
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Ruan T, Sun Y, Zhang J, Sun J, Liu W, Prinz RA, Peng D, Liu X, and Xu X
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- Animals, Intercellular Junctions genetics, Intercellular Junctions metabolism, Intercellular Junctions virology, Lung pathology, Lung virology, Mice, Alveolar Epithelial Cells metabolism, Alveolar Epithelial Cells virology, Influenza A Virus, H5N1 Subtype, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism
- Abstract
The H5N1 subtype of the avian influenza virus causes sporadic but fatal infections in humans. H5N1 virus infection leads to the disruption of the alveolar epithelial barrier, a pathologic change that often progresses into acute respiratory distress syndrome (ARDS) and pneumonia. The mechanisms underlying this remain poorly understood. Here we report that H5N1 viruses downregulate the expression of intercellular junction proteins (E-cadherin, occludin, claudin-1, and ZO-1) in several cell lines and the lungs of H5N1 virus-infected mice. H5N1 virus infection activates TGF-β-activated kinase 1 (TAK1), which then activates p38 and ERK to induce E3 ubiquitin ligase Itch expression and to promote occludin ubiquitination and degradation. Inhibition of the TAK1-Itch pathway restores the intercellular junction structure and function in vitro and in the lungs of H5N1 virus-infected mice. Our study suggests that H5N1 virus infection impairs the alveolar epithelial barrier by downregulating the expression of intercellular junction proteins at the posttranslational level., (© 2022. The Author(s).)
- Published
- 2022
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9. Treatment differences at high volume centers and low volume centers in non-metastatic and metastatic adrenocortical carcinoma.
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MacKinney EC, Holoubek SA, Khokar AM, Kuchta KM, Moo-Young TA, Prinz RA, and Winchester DJ
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- Combined Modality Therapy, Hospitals, High-Volume, Humans, Length of Stay, Retrospective Studies, Adrenal Cortex Neoplasms therapy, Adrenocortical Carcinoma surgery
- Abstract
Background: Adrenocortical carcinoma (ACC) is rare with poor survival. Do treatment and outcomes vary by volume?, Methods: NCDB (2004-2017) was searched for patients with ACC. High-volume centers (HVCs) were defined by ≥ 15 ACC and low-volume centers by ≤ 7 total cases. Multivariable Cox and logistic regression analysis were performed., Results: ACC patients at HVCs were significantly more likely to have surgery, chemotherapy, and had lower 90-day readmission. HVCs were significantly more likely than LVCs to administer chemotherapy to surgical NonMetastatic (NM)-ACC patients. There was no significant difference in overall survival (OS), 90-day mortality, length of stay, or radiation treatments between the two. Operative Metastatic (M)-ACC at HVC had significantly improved OS, more chemotherapy administered, and lower 90-day mortality., Conclusion: NM-ACC and M-ACC treated at HVCs were more likely to have surgery and multimodality therapy. NM-ACC having surgery at HVCs and LVCs had similar OS. M-ACC at HVCs had improved OS and 90-day mortality., (Copyright © 2022. Published by Elsevier Inc.)
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- 2022
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10. Uric acid accumulation in DNA-damaged tumor cells induces NKG2D ligand expression and antitumor immunity by activating TGF-β-activated kinase 1.
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Wang J, Liu K, Xiao T, Liu P, Prinz RA, and Xu X
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- Animals, DNA, DNA Damage, Ligands, MAP Kinase Kinase Kinases, Mice, NK Cell Lectin-Like Receptor Subfamily K genetics, NK Cell Lectin-Like Receptor Subfamily K metabolism, Uric Acid pharmacology
- Abstract
DNA damage by genotoxic drugs such as gemcitabine and 5-fluorouracil (5-FU) activates the ataxia telangiectasia, mutated (ATM)-Chk pathway and induces the expression of NKG2D ligands such as the MHC class I-related chain A and B (MICA/B). The mechanisms underlying this remain incompletely understood. Here we report that xanthine oxidoreductase (XOR), a rate-limiting enzyme that produces uric acid in the purine catabolism pathway, promotes DNA damage-induced MICA/B expression. Inhibition of the ATM-Chk pathway blocks genotoxic drug-induced uric acid production, TGF-β-activated kinase 1 (TAK1) activation, ERK phosphorylation, and MICA/B expression. Inhibition of uric acid production by the XOR inhibitor allopurinol blocks DNA damage-induced TAK1 activation and MICA/B expression in genotoxic drug-treated cells. Exogenous uric acid activates TAK1, NF-κB, and the MAP kinase pathway. TAK1 inhibition blocks gemcitabine- and uric acid-induced MAP kinase activation and MICA/B expression. Exogenous uric acid in its salt form, monosodium urate (MSU), induces MICA/B expression and sensitizes tumor cells to NK cell killing. MSU immunization with irradiated murine breast cancer cell line RCAS-Neu retards breast cancer growth in syngeneic breast cancer models and delays breast cancer development in a somatic breast cancer model. Our study suggests that uric acid accumulation plays an important role in activating TAK1, inducing DNA damage-induced MICA/B expression, and enhancing antitumor immunity., Competing Interests: The authors declare that there are no conflicts of interest, (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Published
- 2022
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11. Overall survival is improved with total thyroidectomy and radiation for male patients and patients older than 55 with T2N0M0 Stage 1 classic papillary thyroid cancer.
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MacKinney EC, Kuchta KM, Winchester DJ, Khokar AM, Holoubek SA, Moo-Young TA, and Prinz RA
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- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Female, Gonadal Steroid Hormones, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Staging, Propensity Score, Radiotherapy, Adjuvant methods, Radiotherapy, Adjuvant statistics & numerical data, Risk Factors, Thyroid Cancer, Papillary diagnosis, Thyroid Cancer, Papillary mortality, Thyroid Gland pathology, Thyroid Gland surgery, Thyroid Neoplasms diagnosis, Thyroid Neoplasms mortality, Treatment Outcome, Young Adult, Iodine Radioisotopes therapeutic use, Thyroid Cancer, Papillary therapy, Thyroid Neoplasms therapy, Thyroidectomy methods
- Abstract
Background: We examine whether surgery extent and radiation administration affect overall survival for cT2N0M0 classic papillary thyroid cancer according to age and sex., Methods: Patients with cT2N0M0 classic papillary thyroid cancer tumors in the National Cancer Data Base (2004-2016) were selected. Multivariable Cox regression analysis compared patients (combined male + female cohorts) having lobectomy to those having total thyroidectomy with or without radiation (primarily radioactive iodine) for ages: 18 to 45, 46 to 55, and >55 years. In addition, 1:1 propensity score matching and Kaplan-Meier curves with 10-year overall survival estimates, and log-rank test were stratified by age and sex., Results: Lobectomy had equivalent overall survival to total thyroidectomy without and with radiation for patients (combined male + female cohorts) aged 18 to 45 and 46 to 55 years on multivariable analysis. On propensity score matching there was overall survival advantage for total thyroidectomy with radiation over both lobectomy and total thyroidectomy for men (ages 18-90+ combined) and overall survival advantage in patients (combined male + female cohort) aged >55 years having total thyroidectomy with radiation versus lobectomy. On propensity score matching there were no overall survival differences in women (ages 18-90+ combined) or patients (combined male + female cohort) aged 18 to 45 and 46 to 55 years having either lobectomy, total thyroidectomy, or total thyroidectomy with radiation., Conclusion: For cT2N0M0 classic papillary thyroid cancer, total thyroidectomy with radiation improves 10-year overall survival for patients (combined male + female cohort) aged >55 years and men (ages 18-90+ combined)., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
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12. Radioactive iodine does not improve overall survival for patients with aggressive variants of papillary thyroid carcinoma less than 2 cm.
- Author
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Holoubek SA, MacKinney EC, Khokar AM, Kuchta KM, Winchester DJ, Prinz RA, and Moo-Young TA
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- Adult, Aged, Female, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Radiotherapy, Adjuvant methods, Radiotherapy, Adjuvant statistics & numerical data, Retrospective Studies, Thyroid Cancer, Papillary mortality, Thyroid Cancer, Papillary pathology, Thyroid Gland pathology, Thyroid Gland surgery, Thyroid Neoplasms mortality, Thyroid Neoplasms pathology, Time Factors, Tumor Burden, Iodine Radioisotopes therapeutic use, Thyroid Cancer, Papillary therapy, Thyroid Neoplasms therapy, Thyroidectomy statistics & numerical data
- Abstract
Background: Tall cell and diffuse sclerosing variants of papillary thyroid cancer are associated with aggressive features. Radioactive iodine after total thyroidectomy is poorly studied., Methods: Patients ≥18 years in the National Cancer Data Base from 2004 to 2016 with classic papillary thyroid cancer, tall cell, or diffuse sclerosing 1 mm to 40 mm were identified. Logistic regression identified factors associated with aggressive features. Overall survival was assessed using Kaplan-Meier method and log-rank tests, after propensity score matching for clinicopathological and treatment variables., Results: A total of 155,940 classic papillary thyroid cancer patients, 4,011 tall cell, and 507 diffuse sclerosing were identified. Tall cell patients represented an increasing proportion of the study population during the analysis period, whereas diffuse sclerosing and classic papillary thyroid cancer patients showed a statistically significant decline. Extrathyroidal extension and nodal involvement were more prevalent among tall cell and diffuse sclerosing patients when compared to those diagnosed with classic papillary thyroid cancer (P < .01). Adjuvant radioactive iodine was less frequently used in patients with classic papillary thyroid cancer when compared to tall cell and diffuse sclerosing patients (42.6% vs 62.4%, 59.0%; P < .001, respectively). Aggressive variants receiving total thyroidectomy versus total thyroidectomy + radioactive iodine propensity score matched across clinicopathologic variables were analyzed. There was no difference in overall survival between the 2 treatment groups for tumors <2 cm (01-1.0 cm, 92.2% vs 84.8%; P = .98); (1.0-2.0 cm, 72.7% vs 88.1%; P = .82). However, overall survival was improved for total thyroidectomy + radioactive iodine propensity score matched patients with tumor sizes 21 to 40 mm versus total thyroidectomy (83.4% vs 70.0%, P = .004)., Conclusion: For aggressive tumor variants ≤2 cm treated with total thyroidectomy, there is no overall survival advantage provided by the addition of adjuvant radioactive iodine., (Copyright © 2021. Published by Elsevier Inc.)
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- 2022
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13. Tips for authors of surgical manuscripts from senior reviewers.
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Malangoni MA, Evans DB, Prinz RA, Hodin RA, Rege R, and Harken AH
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- Editorial Policies, Surveys and Questionnaires, Authorship, Peer Review, Research, Periodicals as Topic
- Published
- 2021
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14. Inhibition of the sonic hedgehog pathway activates TGF-β-activated kinase (TAK1) to induce autophagy and suppress apoptosis in thyroid tumor cells.
- Author
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Li S, Wang J, Lu Y, Zhao Y, Prinz RA, and Xu X
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- Apoptosis, Autophagy, Hedgehog Proteins metabolism, Humans, Signal Transduction, Transfection, Hedgehog Proteins antagonists & inhibitors, Thyroid Gland metabolism, Transforming Growth Factor beta metabolism
- Abstract
The sonic hedgehog (Shh) pathway is highly activated in a variety of malignancies and plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. Our recent study showed that the inhibitors of the Shh pathway such as cyclopamine (CP), a Smothened (SMO) inhibitor, and GANT61, a Gli1 inhibitor, have modest inhibitory effects on thyroid tumor cell proliferation and tumor growth. The objective of this study was to determine whether autophagy was induced by inhibition of the Shh pathway and could negatively regulate GANT61-induced apoptosis. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 induced autophagy in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines; whereas Gli1 overexpression suppressed autophagy. Mechanistic investigation revealed that inhibition of the Shh pathway activated TAK1 and its two downstream kinases, the c-Jun-terminal kinase (JNK) and AMP-activated protein kinase (AMPK). GANT61-induced autophagy was blocked by TAK1 siRNA and the inhibitors of TAK1 (5Z-7-oxozeaenol, 5Z), JNK (SP600125), and AMPK (Compound C, CC). Inhibition of autophagy by chloroquine and 5Z and by TAK1 and Beclin-1 siRNA enhanced GANT61-induced apoptosis and its antiproliferative activity. Our study has shown that inhibition of the Shh pathway induces autophagy by activating TAK1, whereas autophagy in turn suppresses GANT61-induced apoptosis. We have uncovered a previously unrecognized role of TAK1 in Shh pathway inhibition-induced autophagy and apoptosis.
- Published
- 2021
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15. Radioactive iodine-125 seed localization as an aid in reoperative neck surgery.
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Bortz MD, Khokar A, Winchester DJ, Moo-Young TA, Ecanow DB, Ecanow JS, and Prinz RA
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- Adult, Aged, Cohort Studies, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local diagnostic imaging, Reoperation, Thyroid Cancer, Papillary diagnostic imaging, Thyroid Neoplasms diagnostic imaging, Iodine Radioisotopes, Neck Dissection, Neoplasm Recurrence, Local surgery, Thyroid Cancer, Papillary surgery, Thyroid Neoplasms surgery, Thyroidectomy
- Abstract
Background: Scarring and disrupted tissue planes add to already-complex neck anatomy and make localization of nonpalpable pathology difficult in cervical endocrine reoperations. We describe the use of radioactive iodine-125 seed localization (RSL) in 6 patients with metastatic papillary thyroid carcinoma (PTC) and 2 with recurrent hyperparathyroidism., Methods: Eight patients had 2-D ultrasound-guided RSL of the target lesion, 0-3 days preoperatively. Intraoperative gamma probe (Neoprobe) was used to plan incision placement and localize the implanted seed. Recorded operative variables included: number of lymph nodes (LNs) harvested, estimated blood loss (EBL), operative time, length of stay (LOS) and RSL and operative complications., Results: All patients had successful resection of the targeted area and removal of the radioactive seed. There was no seed migration. Two complications occurred in the thyroid group., Conclusion: Radioactive iodine 125 seeds facilitate successful localization of endocrine pathology during reoperative cervical procedures., Competing Interests: Declaration of competing interest No external sources of funding are acknowledged. There are no conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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16. Extrathyroidal extension predicts negative clinical outcomes in papillary thyroid cancer.
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Bortz MD, Kuchta K, Winchester DJ, Prinz RA, and Moo-Young TA
- Subjects
- Adult, Clinical Decision-Making, Databases, Factual statistics & numerical data, Datasets as Topic, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Invasiveness pathology, Neoplasm Staging, Retrospective Studies, Thyroid Cancer, Papillary diagnosis, Thyroid Cancer, Papillary secondary, Thyroid Cancer, Papillary surgery, Thyroid Gland surgery, Thyroid Neoplasms diagnosis, Thyroid Neoplasms pathology, Thyroid Neoplasms surgery, Thyroidectomy, United States, Lymphatic Metastasis pathology, Thyroid Cancer, Papillary mortality, Thyroid Gland pathology, Thyroid Neoplasms mortality
- Abstract
Background: The eighth edition American Joint Committee on Cancer tumor-node-metastasis staging for well-differentiated thyroid cancers, no longer considers "minimal" extrathyroidal extension for tumor staging. This change prompted us to examine the effect of extrathyroidal extension on patient outcomes., Methods: Patients (n = 177,497) in the 2016 National Cancer Database with classic papillary thyroid cancer were evaluated to determine the effect of extrathyroidal extension on overall survival and risk for nodal and distant metastases. Kaplan-Meier curves with the log-rank test were used to evaluate survival differences. Multivariable Cox and logistic regression analyses included relevant clinicopathologic variables (e.g. age, sex, race, and Charlson Comorbidity Index)., Results: Patients with "minimal" extrathyroidal extension had worse survival versus patients with no extrathyroidal extension (10-year survival 89.3% vs 93.1%, hazard ratio 1.23; 95% confidence interval, 1.13-1.35; P < .001). Any extrathyroidal extension was associated with higher risks for lymph node (odds ratio 2.78; 95% confidence interval, 2.69-2.87) and distant metastasis (odds ratio 3.5; 95% confidence interval, 3.05-4.04). These associations persisted when comparing "micro" (extension into the thyroid capsule) versus none for nodal risk (odds ratio 1.25; 95% confidence interval, 1.18-1.33) and distant metastasis (OR 1.52; 95% confidence interval, 1.11-2.09)., Conclusion: All levels of extrathyroidal extension, including microscopic, were associated with increased risk for nodal and distant metastasis. Both minimal and macroscopic extrathyroidal extension were also associated with decreased overall survival. Such findings have the potential to affect the clinical decision making for patients diagnosed with papillary thyroid cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
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17. Inhibition of porcine epidemic diarrhea virus (PEDV) replication by A77 1726 through targeting JAK and Src tyrosine kinases.
- Author
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Li X, Sun J, Prinz RA, Liu X, and Xu X
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- Animals, Chlorocebus aethiops, Crotonates, Gene Expression, Janus Kinase 2 genetics, Nitriles, Phosphorylation drug effects, Porcine epidemic diarrhea virus physiology, STAT3 Transcription Factor metabolism, Toluidines, Vero Cells, src-Family Kinases genetics, Aniline Compounds pharmacology, Hydroxybutyrates pharmacology, Janus Kinase 2 metabolism, Porcine epidemic diarrhea virus drug effects, Protein Kinase Inhibitors pharmacology, Virus Replication drug effects, src-Family Kinases metabolism
- Abstract
Porcine epidemic diarrhea (PED) virus (PEDV) is a coronavirus that primarily infects porcine intestinal epithelial cells and causes severe diarrhea and high fatality in piglets. A77 1726 is the active metabolite of leflunomide, a clinically approved anti-rheumatoid arthritis (RA) drug. A77 1726 inhibits the activity of protein tyrosine kinases (PTKs), p70 S6 kinase (S6K1), and dihydroorotate dehydrogenase (DHO-DHase). Whether A77 1726 can control coronavirus infections has not been investigated. Here we report that A77 1726 effectively restricted PEDV replication by inhibiting Janus kinases (JAKs) and Src kinase activities but not by inhibiting DHO-DHase and S6K1 activities. Overexpression of Src, JAK2 or its substrate STAT3 enhanced PEDV replication and attenuated the antiviral activity of A77 1726. Our study demonstrates for the first time the ability of A77 1726 to control coronavirus replication by inhibiting PTK activities. Leflunomide has potential therapeutic value for the control of PEDV and other coronavirus infections., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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18. In Vitro and In Vivo Antiviral Activity of Gingerenone A on Influenza A Virus Is Mediated by Targeting Janus Kinase 2.
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Wang J, Prinz RA, Liu X, and Xu X
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- A549 Cells, Animals, Cell Line, Dogs, Female, HEK293 Cells, Humans, Imidazoles pharmacology, Influenza A Virus, H1N1 Subtype growth & development, Influenza A Virus, H5N1 Subtype growth & development, Influenza A Virus, H9N2 Subtype growth & development, Madin Darby Canine Kidney Cells, Mice, Mice, Inbred C57BL, Nitriles, Piperazines pharmacology, Pyrazoles pharmacology, Pyrimidines, Ribosomal Protein S6 Kinases, 70-kDa antagonists & inhibitors, Virus Replication drug effects, Antiviral Agents pharmacology, Diarylheptanoids pharmacology, Influenza A Virus, H1N1 Subtype drug effects, Influenza A Virus, H5N1 Subtype drug effects, Influenza A Virus, H9N2 Subtype drug effects, Janus Kinase 2 antagonists & inhibitors
- Abstract
Janus kinase (JAK) inhibitors have been developed as novel immunomodulatory drugs and primarily used for treating rheumatoid arthritis and other inflammatory diseases. Recent studies have suggested that this category of anti-inflammatory drugs could be potentially useful for the control of inflammation "storms" in respiratory virus infections. In addition to their role in regulating immune cell functions, JAK1 and JAK2 have been recently identified as crucial cellular factors involved in influenza A virus (IAV) replication and could be potentially targeted for antiviral therapy. Gingerenone A (Gin A) is a compound derived from ginger roots and a dual inhibitor of JAK2 and p70 S6 kinase (S6K1). Our present study aimed to determine the antiviral activity of Gin A on influenza A virus (IAV) and to understand its mechanisms of action. Here, we reported that Gin A suppressed the replication of three IAV subtypes (H1N1, H5N1, H9N2) in four cell lines. IAV replication was also inhibited by Ruxolitinib (Rux), a JAK inhibitor, but not by PF-4708671, an S6K1 inhibitor. JAK2 overexpression enhanced H5N1 virus replication and attenuated Gin A-mediated antiviral activity. In vivo experiments revealed that Gin A treatment suppressed IAV replication in the lungs of H5N1 virus-infected mice, alleviated their body weight loss, and prolonged their survival. Our study suggests that Gin A restricts IAV replication by inhibiting JAK2 activity; Gin A could be potentially useful for the control of influenza virus infections.
- Published
- 2020
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19. The Gli1-Snail axis contributes to Salmonella Typhimurium-induced disruption of intercellular junctions of intestinal epithelial cells.
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Liu W, Ruan T, Ji X, Ran D, Sun J, Shi H, Prinz RA, Sun J, Pan Z, Jiao X, and Xu X
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- Animals, Caco-2 Cells, Female, HT29 Cells, HeLa Cells, Humans, Mice, Mice, Inbred C57BL, Signal Transduction, Snail Family Transcription Factors metabolism, Zinc Finger Protein GLI1 metabolism, Epithelial Cells microbiology, Intestinal Mucosa microbiology, Intestinal Mucosa pathology, Salmonella typhimurium pathogenicity, Snail Family Transcription Factors genetics, Zinc Finger Protein GLI1 genetics
- Abstract
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular pathogen that damages gastrointestinal tissue and causes severe diarrhoea. The mechanisms by which Salmonella disrupts epithelial barrier and increases the paracellular permeability are incompletely understood. Our present study aims to determine the role of Gli1, a transcription factor activated in the sonic hedgehog (Shh) pathway, in decreasing the levels of apical junction proteins in a Salmonella-infected human colonic epithelial cancer cell line, Caco-2, and in the intestinal tissue of Salmonella-infected mice. Here, we report that S. Typhimurium increased the mRNA and protein levels of Gli1 and Snail, a downstream transcription factor that plays an important role in the epithelial-to-mesenchymal transition (EMT). S. Typhimurium also decreased the levels of E-cadherin and three tight junction proteins (ZO-1, claudin-1, and occludin). Gli1 siRNA and GANT61, a Gli1-specific inhibitor, blocked S. Typhimurium-induced Snail expression, restored the levels of E-cadherin and tight junction proteins, and prevented S. Typhimurium-increased paracellular permeability. Further study showed that Gli1 was cross-activated by the MAP and PI-3 kinase pathways. S. Typhimurium devoid of sopB, an effector of the Type 3 secretion system (T3SS) responsible for AKT activation, was unable to induce Snail expression and to decrease the expression of apical junction proteins. Our study uncovered a novel role of Gli1 in mediating the Salmonella-induced disruption of the intestinal epithelial barrier., (© 2020 John Wiley & Sons Ltd.)
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- 2020
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20. A77 1726, the active metabolite of the anti-rheumatoid arthritis drug leflunomide, inhibits influenza A virus replication in vitro and in vivo by inhibiting the activity of Janus kinases.
- Author
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Wang J, Sun J, Hu J, Wang C, Prinz RA, Peng D, Liu X, and Xu X
- Subjects
- A549 Cells, Animals, Arthritis, Rheumatoid drug therapy, Cell Line, Cell Line, Tumor, Crotonates, Dogs, Female, Humans, Influenza, Human drug therapy, Influenza, Human metabolism, Madin Darby Canine Kidney Cells, Mice, Mice, Inbred C57BL, Nitriles, Orthomyxoviridae Infections metabolism, Toluidines, Aniline Compounds pharmacology, Antirheumatic Agents pharmacology, Hydroxybutyrates pharmacology, Influenza A virus drug effects, Janus Kinases antagonists & inhibitors, Leflunomide pharmacology, Orthomyxoviridae Infections drug therapy, Virus Replication drug effects
- Abstract
The newly reassorted IAV subtypes from zoonotic reservoirs respond poorly to current vaccines and antiviral therapy. There is an unmet need in developing novel antiviral drugs for better control of IAV infection. The cellular factors that are crucial for virus replication have been sought as novel molecular targets for antiviral therapy. Recent studies have shown that Janus kinases (JAK), JAK1, and JAK2, play an important role in IAV replication. Leflunomide is an anti-inflammatory drug primarily used for treating rheumatoid arthritis (RA). Prior studies suggest that A77 1726, the active metabolite of leflunomide, inhibits the activity of JAK1 and JAK3. Our current study aims to determine if A77 1726 can function as a JAK inhibitor to control IAV infection. Here, we report that A77 1726 inhibited the replication of three IAV subtypes(H5N1, H1N1, H9N2)in three cell types (chicken embryonic fibroblasts, A549, and MDCK). A77 1726 inhibited JAK1, JAK2, and STAT3 tyrosine phosphorylation. Similar observations were made with Ruxolitinib (Rux), a JAK-specific inhibitor. JAK2 overexpression enhanced H5N1 virus replication and compromised the antiviral activity of A77 1726. Leflunomide inhibited virus replication in the lungs of IAV-infected mice, alleviated their body weight loss, and prolonged their survival. Our study demonstrates for the first time the ability of A77 1726 to inhibit JAK2 activity and suggests that inhibition of JAK activity contributes to its antiviral activity., (© 2020 Federation of American Societies for Experimental Biology.)
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- 2020
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21. H1N1 Influenza Virus Cross-Activates Gli1 to Disrupt the Intercellular Junctions of Alveolar Epithelial Cells.
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Ruan T, Sun J, Liu W, Prinz RA, Peng D, Liu X, and Xu X
- Subjects
- A549 Cells, Alveolar Epithelial Cells drug effects, Animals, Dogs, Humans, Influenza A Virus, H1N1 Subtype drug effects, Intercellular Junctions drug effects, Lung metabolism, Madin Darby Canine Kidney Cells, Mice, Inbred C57BL, Mitogen-Activated Protein Kinases metabolism, Models, Biological, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Pyridines pharmacology, Pyrimidines pharmacology, Signal Transduction drug effects, Snail Family Transcription Factors metabolism, Alveolar Epithelial Cells metabolism, Alveolar Epithelial Cells microbiology, Influenza A Virus, H1N1 Subtype physiology, Intercellular Junctions metabolism, Zinc Finger Protein GLI1 metabolism
- Abstract
Influenza A virus (IAV) primarily infects the airway and alveolar epithelial cells and disrupts the intercellular junctions, leading to increased paracellular permeability. Although this pathological change plays a critical role in lung tissue injury and secondary infection, the molecular mechanism of IAV-induced damage to the alveolar barrier remains obscure. Here, we report that Gli1, a transcription factor in the sonic hedgehog (Shh) signaling pathway, is cross-activated by the MAP and PI3 kinase pathways in H1N1 virus (PR8)-infected A549 cells and in the lungs of H1N1 virus-infected mice. Gli1 activation induces Snail expression, which downregulates the expression of intercellular junction proteins, including E-cadherin, ZO-1, and Occludin, and increases paracellular permeability. Inhibition of the Shh pathway restores the levels of Snail and intercellular junction proteins in H1N1-infected cells. Our study suggests that Gli1 activation plays an important role in disrupting the intercellular junctions and in promoting the pathogenesis of H1N1 virus infections., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2020
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22. Trends in nonoperative management of papillary thyroid microcarcinoma.
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Holoubek SA, Yan H, Kuchta KM, Winchester DJ, Moo-Young TA, and Prinz RA
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- Carcinoma, Papillary surgery, Female, Humans, Logistic Models, Male, Medical Oncology methods, Medical Oncology statistics & numerical data, Middle Aged, Prevalence, Surgical Oncology methods, Surgical Oncology statistics & numerical data, Survival Rate, Thyroid Neoplasms surgery, United States epidemiology, Carcinoma, Papillary epidemiology, Carcinoma, Papillary therapy, Thyroid Neoplasms epidemiology, Thyroid Neoplasms therapy
- Abstract
Background: In 2010, a Japanese trial of nonoperative management for papillary thyroid microcarcinomas (PTmC) was published. This study determines if the prevalence of nonoperative management in the United States has changed and if there are predictors of this approach., Methods: Patients treated for PTmC between 2004 and 2015 in the National Cancer Data Base were identified. Inclusion criteria were: classic or follicular variant papillary cancer histology, tumor size 1 to 10 mm, cN0 disease and no extrathyroidal extension or metastatic disease. Nonoperative management was assessed over time and compared between 2004-2010 and 2010-2015. Logistic regression identified factors associated with nonoperative management., Results: Of 65 381 PTmC patients, 344 (0.5%) were treated nonoperatively. The annual rate of nonoperative management was similar at 0.6% in 2004 to 0.4% in 2010 (P = .755) but increased to 0.9% in 2015 (P < .001). There was no difference in patient age, race, comorbidities, or reason for nonoperative management between the two periods. Academic centers managed more patients nonoperatively. Multivariable logistic regression suggests older age, facility type, location, Hispanic, Asian, and Native American ethnicity were associated with nonoperative management., Conclusion: The vast majority of PTmC in the United States is treated with an operation. A small but significant increase in nonoperative management occurred between 2004-2010 and 2010-2015., (© 2020 Wiley Periodicals, Inc.)
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- 2020
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23. Increasing trend of bilateral neck exploration in primary hyperparathyroidism.
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Khokar AM, Kuchta KM, Moo-Young TA, Winchester DJ, and Prinz RA
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- Aged, Decision Making, Female, Humans, Hyperparathyroidism, Primary diagnostic imaging, Male, Middle Aged, Retrospective Studies, Hyperparathyroidism, Primary surgery, Minimally Invasive Surgical Procedures trends, Parathyroidectomy trends
- Abstract
Background: Bilateral neck exploration was the standard operation for primary hyperparathyroidism. With improvements in preoperative localization and use of intraoperative PTH (ioPTH) monitoring, minimally invasive unilateral neck exploration has been widely adopted. This study evaluates the trend in parathyroidectomies for primary hyperparathyroidism., Methods: Parathyroidectomy for sporadic primary hyperparathyroidism was analyzed from 2010 to 2017. Exclusion criteria included previous neck surgery and concomitant procedures. The operations were classified as unilateral exploration (UE), UE converted to bilateral exploration (BE), or BE. Variables included preoperative and intraoperative factors. Outcomes included persistence, recurrence, permanent hypocalcemia and recurrent laryngeal nerve (RLN) injury., Results: Four hundred thirty-one patients were reviewed. Since 2010, the rate of BE has increased from 30% to 50%. Disease duration, presence of bone disease, negative localization, baseline ioPTH <100, and ≥2 abnormal glands have increased. Mean operative time has not changed over time. Two percent of patients had persistent disease, <1% had recurrent disease, and 2% have had reoperation. Nine percent had temporary hypoparathyroidism, and 15 patients had temporary RLN injury., Conclusions: This study shows an increasing trend in BE for primary hyperparathyroidism. This increase was associated with lower baseline intraoperative parathyroid hormone (ioPTH) levels and smaller gland size. The operative approach for parathyroidectomy should be individualized and surgeons should not hesitate to perform BE when needed., Competing Interests: Declaration of competing interest The authors have no relevant disclosures., (Copyright © 2019. Published by Elsevier Inc.)
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- 2020
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24. Parathyroidectomy is Safe in Elderly Patients: A National Surgical Quality Improvement Program Study.
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Khokar AM, Kuchta KM, Moo-Young TA, Winchester DJ, and Prinz RA
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- Adult, Age Factors, Aged, Aged, 80 and over, Female, Hernia, Inguinal surgery, Herniorrhaphy mortality, Humans, Hyperparathyroidism, Primary surgery, Logistic Models, Male, Middle Aged, Parathyroidectomy mortality, Parathyroidectomy adverse effects, Quality Improvement
- Abstract
Background: With increasing age, the incidence of hyperparathyroidism is increased. This study evaluates parathyroidectomy outcomes in elderly patients., Methods: Primary hyperparathyroidism patients having parathyroidectomy as listed in the 2005-2017 ACS-NSQIP database were separated by age: ≤60, 61-79 and ≥80. Outcomes included complications, 30-day mortality, return to the OR, operating times, and hospital length of stay (LOS). Multivariable logistic regression was used to compare patients 61-79 and ≥80 to those ≤60. Patients ≤60 and ≥80 were propensity score matched using gender, race, BMI, smoking status, steroid use, modified frailty index (mFI), ASA class, procedure, setting, anesthesia, and wound class. Morbidity and mortality were compared to ACS-NSQIP database patients having elective inguinal hernia repair., Results: Of 47,701 patients: 22,220 were ≤60, 22,683 were 61-79, and 2798 were ≥80. Patients ≥80 had more complications (2.3% vs. 1.5% for 61-79 and 1.0% for ≤60, p < 0.01), LOS > 1 day (10.3% vs. 5.8% and 6.7%, p < 0.01), and mortality (0.21% vs. 0.11% and 0.03%, p < 0.01). On multivariable analysis of the overall population, older age, male gender, steroid use, high mFI, outpatient procedure, and general anesthesia increased the risk of complications. On propensity score matched analysis, there was no difference in complications (1.5% vs. 2.2%, p = 0.06) or mortality (0.04% vs. 0.23%, p = 0.12) between patients ≤60 and ≥80. Parathyroidectomy morbidity and mortality was lower than that for elective inguinal hernia repair in patients ≥80 (2.3% vs. 10% and 0.21% vs. 1.1%, p < 0.01)., Conclusions: Parathyroidectomy is a safe operation, offering lower morbidity and mortality than elective hernia repair in all age groups including octogenarians.
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- 2020
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25. Survival with Follicular and Hurthle Cell Microcarcinoma Compared to Papillary Thyroid Microcarcinoma: A Population Study of 84,532 Patients.
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Khokar AM, Holoubek SA, Kuchta KM, Winchester DJ, Prinz RA, and Moo-Young TA
- Subjects
- Adult, Aged, Female, Humans, Lymphatic Metastasis, Male, Middle Aged, Retrospective Studies, Adenoma, Oxyphilic mortality, Carcinoma, Papillary mortality, Thyroid Epithelial Cells pathology, Thyroid Neoplasms mortality
- Abstract
Background: This study compares survival in patients with the rare subtypes of follicular (FTmC) and Hurthle cell (HCmC) microcarcinoma compared to that of papillary thyroid (PTmC) microcarcinoma., Methods: Patients with FTmC and HCmC were selected from the National Cancer Database 2004-2015 and compared with PTmC. Patient clinicopathological characteristics and overall survival (OS) were analyzed. Multivariable logistic and Cox regression analysis evaluated binary outcomes and predictors of survival. A propensity score matched analysis using age, gender, race, extrathyroidal extension (ETE), nodal status, distant metastasis, radiation, and operation was performed to evaluate the difference in OS with FTmC, HCmC, and PTmC., Results: We identified 858 FTmC, 476 HCmC, and 82,056 PTmC. FTmC was less likely to have macroscopic ETE compared to PTmC (2.6% vs. 3.1% p = 0.03), but more likely to have distant metastasis (2.3% vs. 0.2%, p < 0.01). FTmC and HCmC were less likely to have nodal metastasis (2.7%, 2.5% vs. 10.9%, p < 0.01). Ten-year OS was decreased in patients with FTmC (91.4%, p = 0.04) and HCmC (89.8%, p < 0.01) compared to PTmC (93.5%). On multivariable analysis, histology was not associated with OS. With HCmC, older age (OR 1.13, p < 0.01) and male gender (OR 2.72, p = 0.03) were associated with decreased OS. In propensity matched analysis, there was no difference in 10-year OS with FTmC and PTmC (91.4% vs. 93.7%, p = 0.54), but HCmC had decreased OS compared to PTmC (89.8% vs. 94.3%, p = 0.04)., Conclusions: Patients with FTmC have comparable OS to those with PTmC, but HCmC has decreased OS especially in older and male patients.
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- 2020
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26. Thyroid Lobectomy for T1b-T2 Papillary Thyroid Cancer with High-Risk Features.
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Suman P, Razdan SN, Wang CE, Tulchinsky M, Ahmed L, Prinz RA, and Winchester DJ
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- Adult, Female, Humans, Male, Middle Aged, Neoplasm Staging, Retrospective Studies, Risk Factors, Thyroid Cancer, Papillary pathology, Thyroid Neoplasms pathology, Thyroid Cancer, Papillary surgery, Thyroid Neoplasms surgery, Thyroidectomy methods
- Abstract
Background: Thyroid lobectomy (TL) has been proposed as definitive surgical treatment for papillary thyroid cancers (PTC) up to 4 cm. This study evaluates the use and appropriateness of TL for T1b and T2 PTC., Study Design: The National Cancer Database was interrogated for adult patients having TL for T1b-T2 PTC between 2004 and 2014. Patients who should have undergone total thyroidectomy (TT) instead of lobectomy based on high-risk tumor features were identified. The 2 groups were compared for clinical and demographic characteristics, and overall survival., Results: Of 8,083 patients undergoing lobectomy, 1,552 patients had high-risk features and should have undergone TT. These included 194 with cN1, 571 with pN1, 307 with lymphovascular invasion (LVI), 645 with extra thyroidal extension (ETE), 567 with positive margins, 42 with poorly differentiated PTC, and 25 with M1 disease. At 10 years of follow-up, 92.4% of appropriate lobectomy (aTL) patients were alive compared with 88.5% of inappropriate lobectomy (iTL) patients (p < 0.001). On univariate and multivariable Cox survival analysis, age greater than 45 years, male sex, comorbidities, government or no insurance, low income, and tumor size >2 cm were associated with poorer survival (all p < 0.05). Thyroid lobectomy patients with high-risk features had significantly higher mortality on unadjusted (hazard ratio [HR] 1.98, 95% CI 1.52 to 2.59, p < 0.001) and adjusted survival analysis (HR 1.97, 95% CI 1.51 to 2.58, p < 0.001). Total thyroidectomy with radioiodine treatment had improved overall survival in comparison to iTL (HR 0.65, 95% CI 0.51 to 0.83, p < 0.001)., Conclusions: A substantial number of patients (19.2%) with tumor size >1 cm and high-risk features undergo thyroid lobectomy for PTC. Exclusion of high-risk features is important when adopting lobectomy as the definitive surgical therapy for T1b and T2 PTC because they have a potential adverse effect on long-term survival., (Copyright © 2019 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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27. Aggressive variants of papillary thyroid microcarcinoma are associated with high-risk features, but not decreased survival.
- Author
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Holoubek SA, Yan H, Khokar AH, Kuchta KM, Winchester DJ, Prinz RA, and Moo-Young TA
- Subjects
- Adult, Aged, Carcinoma, Papillary pathology, Carcinoma, Papillary therapy, Female, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Lymphatic Metastasis pathology, Male, Middle Aged, Prognosis, Survival Rate, Thyroid Neoplasms pathology, Thyroid Neoplasms therapy, Treatment Outcome, Carcinoma, Papillary mortality, Iodine Radioisotopes administration & dosage, Lymphatic Metastasis diagnosis, Thyroid Gland pathology, Thyroid Neoplasms mortality, Thyroidectomy
- Abstract
Background: This study compares pathologic features and overall survival of classic versus aggressive variants of papillary thyroid microcarcinoma (PMTC)., Methods: Patients ≥18 years in the National Cancer Data Base (2004-2015) with the subtypes of classic (cPTMC), tall cell (mTCV), or diffuse sclerosing (mDSV) PTC (≤1 cm) were identified. Overall survival was analyzed by Kaplan-Meier and propensity matched for clinicopathologic and treatment variables., Results: There were 82,056 cPTMC patients, 923 mTCV, and 219 mDSV. Extrathyroidal extension and nodal involvement were more frequent in mTCV and mDSV versus cPTMC (P < .01). mTCV had more distant metastases than cPTMC (P = .02). On multivariable analysis, mTCV (odds ratio 4.19 [3.58-4.92], P < .001) and mDSV (odds ratio 2.76 [1.92-3.97]; P < .01) histologies were predictors of extrathyroidal extension. mTCV was an independent predictor of nodal metastases (odds ratio 1.51 [1.25-1.83], P < .01). Total thyroidectomy and radioactive iodine treatment were more commonly used in mTCV and mDSV patients when compared with cPTMC patients. Despite more aggressive features and more aggressive treatment in mTCV and mDSV patients, there was no difference in overall survival when compared with propensity-matched cPTMC patients., Conclusion: Although mTCV and mDSV have more aggressive pathologic features and were treated more aggressively, there were no differences in overall survival compared with propensity-matched cPTMC patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2020
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28. Toll-like receptor signalling cross-activates the autophagic pathway to restrict Salmonella Typhimurium growth in macrophages.
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Liu W, Zhuang J, Jiang Y, Sun J, Prinz RA, Sun J, Jiao X, and Xu X
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- AMP-Activated Protein Kinases metabolism, Animals, Cell Line, MAP Kinase Kinase Kinases metabolism, Mice, Phosphorylation physiology, RAW 264.7 Cells, TOR Serine-Threonine Kinases metabolism, Autophagy physiology, Macrophages metabolism, Macrophages microbiology, Salmonella typhimurium growth & development, Signal Transduction physiology, Toll-Like Receptors metabolism
- Abstract
It has been long recognised that activation of toll-like receptors (TLRs) induces autophagy to restrict intracellular bacterial growth. However, the mechanisms of TLR-induced autophagy are incompletely understood. Salmonella Typhimurium is an intracellular pathogen that causes food poisoning and gastroenteritis in humans. Whether TLR activation contributes to S. Typhimurium-induced autophagy has not been investigated. Here, we report that S. Typhimurium and TLRs shared a common pathway to induce autophagy in macrophages. We first showed that S. Typhimurium-induced autophagy in a RAW264.7 murine macrophage cell line was mediated by the AMP-activated protein kinase (AMPK) through activation of the TGF-β-activated kinase (TAK1), a kinase activated by multiple TLRs. AMPK activation led to increased phosphorylation of Unc-51-like autophagy activating kinase (ULK1) at S317 and S555. ULK1 phosphorylation at these two sites in S. Typhimurium-infected macrophages overrode the inhibitory effect of mTOR on ULK1 activity due to mTOR-mediated ULK1 phosphorylation at S757. Lipopolysaccharide (LPS), flagellin, and CpG oligodeoxynucleotide, which activate TLR4, TLR5, and TLR9, respectively, increased TAK1 and AMPK phosphorylation and induced autophagy in RAW264.7 cells and in bone marrow-derived macrophages. However, LPS was unable to induce TAK1 and AMPK phosphorylation and autophagy in TLR4-deficient macrophages. TAK1 and AMPK-specific inhibitors blocked S. Typhimurium-induced autophagy and xenophagy and increased the bacterial growth in RAW264.7 cells. These observations collectively suggest that activation of the TAK1-AMPK axis through TLRs is essential for S. Typhimurium-induced autophagy and that TLR signalling cross-activates the autophagic pathway to clear intracellular bacteria., (© 2019 John Wiley & Sons Ltd.)
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- 2019
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29. Role of TGF-β-activated kinase 1 (TAK1) activation in H5N1 influenza A virus-induced c-Jun terminal kinase activation and virus replication.
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Sheng T, Sun Y, Sun J, Prinz RA, Peng D, Liu X, and Xu X
- Subjects
- Autophagy, HEK293 Cells, Humans, Mitogen-Activated Protein Kinases metabolism, Plant Proteins metabolism, Adaptor Proteins, Signal Transducing metabolism, Host-Pathogen Interactions, Influenza A Virus, H5N1 Subtype growth & development, MAP Kinase Kinase 4 metabolism, Viral Nonstructural Proteins metabolism, Virus Replication
- Abstract
Activation of c-Jun terminal kinase (JNK) by the nonstructural protein 1 (NS1) of the H5N1 subtype of influenza A virus (IAV) plays an important role in inducing autophagy and virus replication. However, the mechanisms of NS1-induced JNK activation remain elusive. Here we first confirmed the ability of H5N1 (A/mallard/Huadong/S/2005) to activate JNK and to induce autophagy in 293T cells, a human embryonic kidney cell line. We further showed that TAK1, MAP kinase kinase 4 (MKK4), and JNK were activated in 293T cells transfected with the NS1 gene of the H5N1 virus. JNK activation by the NS1 protein or by H5N1 virus was blocked by 5Z-7-Oxozeaenol (5Z), a TAK1-specific inhibitor, and by TAK1 siRNA. Further study showed that 5Z and TAK1 siRNA suppressed H5N1 virus-induced autophagy and inhibited virus replication. Our study unveiled a previously unrecognized role of TAK1 in IAV replication, IAV-induced JNK activation, and autophagy., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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30. Degree of hypercalcemia correlates with parathyroidectomy but not with symptoms.
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Yan H, Calcatera N, Moo-Young TA, Prinz RA, and Winchester DJ
- Subjects
- Female, Humans, Male, Middle Aged, Retrospective Studies, Hypercalcemia complications, Hyperparathyroidism, Primary surgery, Parathyroidectomy statistics & numerical data
- Abstract
Background: Primary hyperparathyroidism (HPT) is an undertreated disease. This study's purpose is to determine if the calcium levels correlate with prevalence of symptoms and surgical treatment in patients with primary HPT., Method: Patients treated in 2006-2015 with serum calcium≥10.0 mg/dL and PTH>65 pg/mL were identified and stratified based on calcium level: 10.0-10.3 (normocalcemia), 10.4-11.2 (moderate), and ≥11.3 (severe) mg/dL. Clinical variables and rates of surgery were compared between the three groups., Results: A total of 2266 patients were identified: 303 with normocalcemia, 1513 with moderate hypercalcemia, and 450 with severe hypercalcemia. All three groups had similar rates of nephrolithiasis (p = 0.10), osteoporosis (p = 0.82), and reduced GFR (p = 0.06). Most patients (85%) had at least one surgical indication, but only 29% underwent parathyroidectomy. Higher calcium levels were correlated with higher surgical rates: 12% for Ca 10.0-10.3, 27% for Ca 10.4-11.2, and 46% for Ca≥11.3 (p < 0.01)., Conclusion: Prevalence of symptoms does not correlate with calcium levels. Patients with normocalcemia and moderate hypercalcemia were equally likely to have a surgical indication, but normocalcemic patients are less likely to receive surgery., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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31. Role of c-Jun terminal kinase (JNK) activation in influenza A virus-induced autophagy and replication.
- Author
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Zhang J, Ruan T, Sheng T, Wang J, Sun J, Wang J, Prinz RA, Peng D, Liu X, and Xu X
- Subjects
- Animals, Anthracenes pharmacology, Cells, Cultured, Chickens, Enzyme Activation drug effects, Host-Pathogen Interactions, Influenza A Virus, H1N1 Subtype physiology, Influenza A Virus, H5N1 Subtype physiology, Influenza A Virus, H9N2 Subtype physiology, Influenza in Birds physiopathology, Influenza in Birds virology, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, Phosphatidylinositol 3-Kinases metabolism, Protein Kinase Inhibitors pharmacology, Signal Transduction, Species Specificity, Viral Nonstructural Proteins metabolism, Autophagy drug effects, Influenza A virus physiology, Influenza in Birds enzymology, JNK Mitogen-Activated Protein Kinases metabolism, Virus Replication drug effects
- Abstract
The non-structural protein 1 (NS1) of different influenza A virus (IAV) strains can differentially regulate the activity of c-Jun terminal kinase (JNK) and PI-3 kinase (PI3K). Whether varying JNK and PI3K activation impacts autophagy and IAV replication differently remains uncertain. Here we report that H5N1 (A/mallard/Huadong/S/2005) influenza A virus induced functional autophagy, as evidenced by increased LC3 lipidation and decreased p62 levels, and the presence of autolysosomes in chicken fibroblast cells. H9N2 (A/chicken/Shanghai/F/98) virus weakly induced autophagy, whereas H1N1 virus (A/PR/8/34, PR8) blocked autophagic flux. H5N1 virus activated JNK but inhibited the PI-3 kinase pathway. In contrast, N9N2 virus infection led to modest JNK activation and strong PI-3 kinase activation; whereas H1N1 virus activated the PI-3 kinase pathway but did not activate JNK. SP600125, a JNK inhibitor, inhibited H5N1 virus-induced autophagy and virus replication in a DF-1 chicken fibroblast cell line. Our study uncovered a previously unrecognized role of JNK in IAV replication and autophagy., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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32. Epigenetic chromatin conformation changes in peripheral blood can detect thyroid cancer.
- Author
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Yan H, Hunter E, Akoulitchev A, Park P, Winchester DJ, Moo-Young TA, and Prinz RA
- Subjects
- Adult, Biomarkers, Tumor blood, Biopsy, Fine-Needle, Female, Humans, Male, Middle Aged, Nucleic Acid Conformation, Predictive Value of Tests, Sensitivity and Specificity, Thyroid Gland, Thyroid Neoplasms blood, Thyroid Nodule genetics, Thyroid Nodule pathology, Thyroid Nodule surgery, Thyroidectomy, Biomarkers, Tumor genetics, Chromatin genetics, Chromosome Aberrations, Epigenesis, Genetic, Thyroid Neoplasms diagnosis
- Abstract
Background: Fine needle aspiration has been the traditional method for diagnosing thyroid cancer. Epigenetic chromatin conformation changes offer an alternative method of diagnosing cancer. The purpose of this study is to evaluate an EpiSwitch assay of epigenetic markers that can be used to diagnose thyroid cancer in blood samples., Methods: From 2014 to 2016, adult patients with thyroid nodules having thyroidectomy were recruited and grouped based on benign, malignant, and atypia of undetermined significance or follicular lesions of undetermined significance fine needle aspiration cytology. Blood samples were collected before surgery. Final pathologic diagnosis was made from the thyroid specimens. Patients' blood samples were analyzed using the EpiSwitch assay, (Oxford Biodynamics, Oxford, UK), and the results were compared with surgical pathology to determine assay performance., Results: In total, 58 patients were recruited: 20 benign, 20 malignant, and 18 atypia or follicular lesions of undetermined significance. An analysis of the malignant and benign fine needle aspiration groups found 6 epigenetic markers for thyroid. A total of 28 (48%) patients had thyroid cancer. The assay was able to correctly identify 25 of the 28 malignant nodules, showing sensitivity of 89.3% and specificity of 66.7%. The positive predictive value for the assay was 71.4%, whereas the negative predictive value was 87.0%., Conclusion: An epigenetic assay of peripheral blood shows high sensitivity in detecting thyroid cancer and provides an additional method for its diagnosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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33. Gingerenone A Sensitizes the Insulin Receptor and Increases Glucose Uptake by Inhibiting the Activity of p70 S6 Kinase.
- Author
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Chen J, Sun J, Prinz RA, Li Y, and Xu X
- Subjects
- 3T3-L1 Cells, Animals, Feedback, Physiological drug effects, Glucose Transporter Type 4 metabolism, Hypoglycemic Agents pharmacology, Insulin pharmacology, Insulin Receptor Substrate Proteins metabolism, Insulin Resistance, Mice, Muscle Fibers, Skeletal drug effects, Phosphatidylinositol 3-Kinases metabolism, Protein Transport drug effects, Proto-Oncogene Proteins c-akt metabolism, Rats, Receptor, Insulin metabolism, Diarylheptanoids pharmacology, Glucose metabolism, Ribosomal Protein S6 Kinases, 70-kDa metabolism
- Abstract
Scope: The bioactive constituents in ginger extract are responsible for anti-hyperglycemic effects and the underlying mechanisms are incompletely understood. Gingerenone A (Gin A) has been identified as an inhibitor of p70 S6 (S6K1), a kinase that plays a critical role in the pathogenesis of insulin resistance. This study aims to evaluate if Gin A can sensitize the insulin receptor by inhibiting S6K1 activity., Methods and Results: Western blot analysis reveals that Gin A induces phosphatidylinositide-3 kinase (PI3K) feedback activation in murine 3T3-L1 adipocytes and rat L6 myotubes, as evidenced by increased AKT
S473 and S6K1T389 but decreases S6S235/236 and insulin receptor substrate 1 (IRS-1)S1101 phosphorylation. Western blot and immunoprecipitation analysis reveal that Gin A increases insulin receptor tyrosine phosphorylation in L6 myotubes and IRS-1 binding to the PI3K in 3T3-L1 adipocytes. Confocal microscopy reveals that Gin A enhances insulin-induced translocation of glucose transporter 4 (GLUT4) into the cell membrane in L6 cells. 2-NBDG (2-N-(Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose) Fluorescent assay reveals that Gin A enhances insulin-stimulated glucose uptake in 3T3-L1 adipocytes and L6 myotubes., Conclusions: Gin A overcomes insulin resistance and increases glucose uptake by inhibiting S6K1 activity. Gin A or other plant-derived S6K1 inhibitors could be developed as novel antidiabetic agents., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2018
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34. Differences in the Impact of Age on Mortality in Well-Differentiated Thyroid Cancer.
- Author
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Yan H, Winchester DJ, Prinz RA, Wang CH, Nakazato Y, and Moo-Young TA
- Subjects
- Adenocarcinoma, Follicular pathology, Adenocarcinoma, Follicular therapy, Adult, Age Factors, Aged, Carcinoma, Papillary pathology, Carcinoma, Papillary therapy, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Iodine Radioisotopes therapeutic use, Male, Middle Aged, Prognosis, Survival Rate, Thyroid Neoplasms pathology, Thyroid Neoplasms therapy, Thyroidectomy, Adenocarcinoma, Follicular mortality, Carcinoma, Papillary mortality, Thyroid Neoplasms mortality
- Abstract
Introduction: Well-differentiated thyroid cancer (WDTC) is unique in that patient age is part of staging. Several studies have shown a need to increase the age threshold in staging for WDTC, but the separate impact of age on prognosis for papillary and follicular carcinomas has not been examined. We hypothesize that age impacts survival differently for papillary and follicular carcinomas., Methods: Patients with invasive papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) between 2004 and 2013 were identified in the National Cancer Database, and were stratified by histologic type. Overall survival (OS) was analyzed using multivariable Cox regression, and the Youden index was used to find the optimal age threshold for both histologies., Results: A total of 204,139 patients with WDTC were identified. Ninety-two percent had PTC, while 7.7% had FTC. The average age was 48.4 years and OS was 96.3%, with a median follow-up of 52.7 months. When analyzing age in 5-year increments, 10-year mortality increased incrementally by 30-50% per age group for PTC, from age < 35 to ≥ 70 years, without an obvious inflection point. However, FTC patients experienced a more than threefold increase in 10-year mortality from age 40-44 years (2.5%) to age 45-49 years (7.9%). The same pattern was found on multivariable Cox regression. The Youden index found the optimal age thresholds were 58.5 years for PTC and 46.2 years for FTC., Conclusion: OS for PTC decreases incrementally with age, but OS for FTC decreases significantly in patients aged 45 years and older. A higher age threshold may inappropriately downstage some high-risk follicular cancer patients.
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- 2018
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35. Thyroid lobectomy is not sufficient for T2 papillary thyroid cancers.
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Rajjoub SR, Yan H, Calcatera NA, Kuchta K, Wang CE, Lutfi W, Moo-Young TA, Winchester DJ, and Prinz RA
- Subjects
- Adult, Aged, Carcinoma, Papillary pathology, Carcinoma, Papillary surgery, Female, Humans, Male, Middle Aged, Retrospective Studies, Thyroid Cancer, Papillary, Thyroid Neoplasms pathology, Thyroid Neoplasms surgery, United States epidemiology, Carcinoma, Papillary mortality, Thyroid Gland pathology, Thyroid Neoplasms mortality, Thyroidectomy
- Abstract
Background: Histologic subtypes of papillary thyroid cancer affect prognosis. The objective of this study was to examine whether survival is affected by extent of surgery for conventional versus follicular-variant papillary thyroid cancer when stratified by tumor size., Methods: Using the National Cancer Data Base, we evaluated 33,816 adults undergoing surgery for papillary thyroid cancer from 2004 to 2008 for 1.0-3.9 cm tumors and clinically negative lymph nodes. Conventional and follicular-variant papillary thyroid cancers were divided into separate groups. Cox regression models stratified by tumor size were used to determine if extent of surgery affected overall survival., Results: A total of 30,981 patients had total thyroidectomy and 2,835 had thyroid lobectomy; 22,899 patients had conventional papillary thyroid cancer and 10,918 had follicular-variant papillary thyroid cancer. On unadjusted KM analysis, total thyroidectomy was associated with improved survival for conventional (P = 0.02) but not for follicular-variant papillary thyroid cancer patients (P = 0.42). For conventional papillary thyroid cancer, adjusted analysis showed total thyroidectomy was associated with improved survival for 2.0-3.9 cm tumors (P = 0.03) but not for 1.0-1.9 cm tumors (P = 0.16). For follicular-variant, lobectomy and total thyroidectomy had equivalent survival for 1.0-1.9 cm (P = 0.45) and 2.0-3.9 cm (P = 0.88) tumors., Conclusion: Tumor size, histologic subtype, and surgical therapy are important factors in papillary thyroid cancer survival. Total thyroidectomy was associated with improved survival in patients with 2.0-3.9 cm conventional papillary thyroid cancer, and should be considered for 2.0-3.9 cm papillary thyroid cancers when preoperative molecular analysis is not used to distinguish conventional from follicular-variant., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2018
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36. Does adjuvant radiation provide any survival benefit after an R1 resections for pancreatic cancer?
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Suss NR, Talamonti MS, Bryan DS, Wang CH, Kuchta KM, Stocker SJ, Bentrem DJ, Roggin KK, Winchester DJ, Marsh R, Prinz RA, Murad FM, and Baker MS
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Pancreatic Ductal mortality, Carcinoma, Pancreatic Ductal surgery, Chemoradiotherapy, Adjuvant, Humans, Middle Aged, Pancreatic Neoplasms mortality, Pancreatic Neoplasms surgery, Radiotherapy, Adjuvant, Retrospective Studies, United States epidemiology, Carcinoma, Pancreatic Ductal radiotherapy, Pancreatic Neoplasms radiotherapy
- Abstract
Background: The benefit of adding external beam radiation to adjuvant chemotherapy in patients that have undergone a margin positive resection for early stage, pancreatic ductal adenocarcinoma has not been determined definitively., Methods: The National Cancer Data Base was queried to evaluate the utility of adjuvant radiation in patients with pathologic stage I-II pancreatic ductal adenocarcinoma who underwent upfront pancreatoduodenectomy with a positive margin (margin positive resection) between 2004 and 2013., Results: In the study, 1,392 patients met inclusion criteria, of whom 263 (18.9%) were lymph node-negative (pathologic stages IA, IB, IIA) and 1,129 (81.1%) were node-positive (pathologic stage IIB); 938 (67.4%) patients received adjuvant radiation and chemotherapy, while 454 (32.6%) received adjuvant chemotherapy alone. Cox modeling stratified by nodal status demonstrated the benefit of radiation to be statistically significant only in node positive patients (hazard ratio 0.81, 95% confidence interval, 0.71-0.93). Node-positive patients receiving adjuvant radiation and chemotherapy had an adjusted median survival of 17.5 months vs 15.2 months for those receiving adjuvant chemotherapy alone (P=.003). In patients who had negative nodes, there was no difference in overall survival with radiation (22.5 vs 23.6 months, P=.511)., Conclusion: Addition of radiation to adjuvant chemotherapy after a margin positive resection confers a survival benefit albeit limited (about 2 months) in patients with node-positive pancreatic head cancer. (Surgery 2017;160:XXX-XXX.)., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2018
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37. Activation of TGF-β-activated kinase 1 (TAK1) restricts Salmonella Typhimurium growth by inducing AMPK activation and autophagy.
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Liu W, Jiang Y, Sun J, Geng S, Pan Z, Prinz RA, Wang C, Sun J, Jiao X, and Xu X
- Subjects
- AMP-Activated Protein Kinases genetics, Enzyme Activation, HeLa Cells, Humans, MAP Kinase Kinase Kinases genetics, Salmonella Infections genetics, Salmonella Infections pathology, Salmonella typhimurium genetics, AMP-Activated Protein Kinases metabolism, Autophagy, MAP Kinase Kinase Kinases metabolism, Salmonella Infections metabolism, Salmonella typhimurium metabolism
- Abstract
Autophagy is a conserved cellular process that functions as a first-line defense to restrict the growth of invading parasitic bacteria. As an intracellular pathogen, Salmonella (S) Typhimurium invades host cells through two Type III secretion systems (T3SS) and resides in the Salmonella-containing vacuole (SCV). When the SCV membrane is perforated and ruptured by T3SS-1, a small portion of the Salmonella egresses from the SCV and replicates rapidly in the nutrient-rich cytosol. Cytosolic Salmonella and those residing in the membrane-damaged SCV are tagged by ubiquitination and marked for autophagy through the ubiquitin-binding adaptor proteins such as p62, NDP52, and optineurin. Prior studies suggest that transient intracellular amino-acid starvation and subsequent inactivation of the mechanistic target of rapamycin (mTOR), a key molecule that phosphorylates Unc-51 like autophagy activating kinase (ULK1) and inhibits its activity, can trigger autophagy in S. Typhimurium-infected cells. Other studies suggest that energy stress in S. Typhimurium-infected cells leads to AMP-activated protein kinase (AMPK) activation and autophagy. In the present study, we report that autophagy was rapidly induced in S. Typhimurium-infected cells, as evidenced by increased LC3 lipidation and decreased p62 levels. However, S. Typhimurium infection drastically increased AKT phosphorylation but decreased S6K1
T389 , 4E-BPT37/46 , and ULK1S757 phosphorylation, suggesting that mTOR activation by AKT is subverted. Further studies showed that AMPK was activated in S. Typhimurium-infected cells, as evidenced by increased ULK1S317 and ACCS79 phosphorylation. AMPK activation was mediated by Toll-like receptor-activated TAK1. Functional studies revealed that AMPK and TAK1 inhibitors accelerated S. Typhimurium growth in HeLa cells. Our results strongly suggest that TAK1 activation leads to AMPK activation, which activates ULK1 by phosphorylating ULK1S317 and suppressing mTOR activity and ULK1S757 phosphorylation. Our study has unveiled a previously unrecognized pathway for S. Typhimurium-induced autophagy.- Published
- 2018
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38. Control of hyperglycemia in male mice by leflunomide: mechanisms of action.
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Chen J, Sun J, Doscas ME, Ye J, Williamson AJ, Li Y, Li Y, Prinz RA, and Xu X
- Subjects
- 3T3-L1 Cells, Aniline Compounds pharmacology, Animals, Blood Glucose metabolism, Cells, Cultured, Crotonates, Glucose metabolism, Glucose Tolerance Test, Hydroxybutyrates pharmacology, Hyperglycemia blood, Leflunomide therapeutic use, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Mice, Transgenic, Nitriles, Obesity blood, Obesity complications, Obesity pathology, Rats, Receptor, Insulin metabolism, Signal Transduction drug effects, Toluidines, Blood Glucose drug effects, Hyperglycemia prevention & control, Leflunomide pharmacology
- Abstract
p70 S6 kinase (S6K1) is a serine/threonine kinase that phosphorylates the insulin receptor substrate-1 (IRS-1) at serine 1101 and desensitizes insulin receptor signaling. S6K1 hyperactivation due to overnutrition leads to hyperglycemia and type 2 diabetes. Our recent study showed that A77 1726, the active metabolite of the anti-rheumatoid arthritis (RA) drug leflunomide, is an inhibitor of S6K1. Whether leflunomide can control hyperglycemia and sensitize the insulin receptor has not been tested. Here we report that A77 1726 increased AKT
S473/T308 and S6K1T389 phosphorylation but decreased S6S235/236 and IRS-1S1101 phosphorylation in 3T3-L1 adipocytes, C2C12 and L6 myotubes. A77 1726 increased insulin receptor tyrosine phosphorylation and binding of the p85 subunit of the PI-3 kinase to IRS-1. A77 1726 enhanced insulin-stimulated glucose uptake in L6 myotubes and 3T3-L1 adipocytes, and enhanced insulin-stimulated glucose transporter type 4 (GLUT4) translocation to the plasma membrane of L6 cells. Finally, we investigated the anti-hyperglycemic effect of leflunomide on ob/ob and high-fat diet (HFD)-induced diabetes mouse models. Leflunomide treatment normalized blood glucose levels and overcame insulin resistance in glucose and insulin tolerance tests in ob/ob and HFD-fed mice but had no effect on mice fed a normal chow diet (NCD). Leflunomide treatment increased AKTS473/T308 phosphorylation in the fat and muscle of ob/ob mice but not in normal mice. Our results suggest that leflunomide sensitizes the insulin receptor by inhibiting S6K1 activity in vitro , and that leflunomide could be potentially useful for treating patients with both RA and diabetes., (© 2018 Society for Endocrinology.)- Published
- 2018
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39. Inhibition of p70 S6 kinase activity by A77 1726 induces autophagy and enhances the degradation of superoxide dismutase 1 (SOD1) protein aggregates.
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Sun J, Mu Y, Jiang Y, Song R, Yi J, Zhou J, Sun J, Jiao X, Prinz RA, Li Y, and Xu X
- Subjects
- AMP-Activated Protein Kinase Kinases, Amino Acid Motifs, Animals, Autophagy-Related Protein 7 genetics, Autophagy-Related Protein 7 metabolism, Autophagy-Related Protein-1 Homolog genetics, Autophagy-Related Protein-1 Homolog metabolism, Cell Line, Crotonates, MAP Kinase Kinase Kinases genetics, MAP Kinase Kinase Kinases metabolism, Mice, Nitriles, Protein Aggregates drug effects, Protein Kinases genetics, Protein Kinases metabolism, Proteolysis drug effects, Ribosomal Protein S6 Kinases, 70-kDa chemistry, Ribosomal Protein S6 Kinases, 70-kDa genetics, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Superoxide Dismutase-1 genetics, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Toluidines, Aniline Compounds pharmacology, Autophagy drug effects, Hydroxybutyrates pharmacology, Ribosomal Protein S6 Kinases, 70-kDa antagonists & inhibitors, Superoxide Dismutase-1 metabolism
- Abstract
Autophagy plays a central role in degrading misfolded proteins such as mutated superoxide dismutase 1 (SOD1), which forms aggregates in motor neurons and is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Autophagy is activated when UNC-51-like kinase 1 (ULK1) is phosphorylated at S555 and activated by AMP-activated protein kinase (AMPK). Autophagy is suppressed when ULK1 is phosphorylated at S757 by the mechanistic target of rapamycin (mTOR). Whether p70 S6 kinase 1 (S6K1), a serine/threonine kinase downstream of mTOR, can also regulate autophagy remains uncertain. Here we report that inhibition of S6K1 by A77 1726, the active metabolite of an anti-inflammatory drug leflunomide, induced mTOR feedback activation and ULK1
S757 phosphorylation in NSC34 cells, a hybrid mouse motoneuron cell line. Unexpectedly, A77 1726 did not suppress but rather induced autophagy by increasing AMPKT172 and ULK1S555 phosphorylation. Similar observations were made with PF-4708671, a specific S6K1 inhibitor, or with S6K1 siRNA. Further studies showed that A77 1726 induced AMPK phosphorylation by activating the TGF-β-activated kinase 1 (TAK1). Functional studies revealed that A77 1726 induced co-localization of mutant SOD1G93A protein aggregates with autophagosomes and accelerated SOD1G93A protein degradation, which was blocked by inhibition of autophagy through autophagy-related protein 7 (ATG7) siRNA. Our study suggests that S6K1 inhibition induces autophagy through TAK1-mediated AMPK activation in NSC34 cells, and that blocking S6K1 activity by a small molecule inhibitor such as leflunomide may offer a new strategy for ALS treatment.- Published
- 2018
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40. Minimally invasive pancreatoduodenectomy: is the incidence of clinically relevant postoperative pancreatic fistula comparable to that after open pancreatoduodenectomy?
- Author
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Kantor O, Pitt HA, Talamonti MS, Roggin KK, Bentrem DJ, Prinz RA, and Baker MS
- Subjects
- Adult, Aged, Cohort Studies, Female, Humans, Incidence, Intention to Treat Analysis, Male, Middle Aged, Pancreaticoduodenectomy methods, United States, Conversion to Open Surgery adverse effects, Laparoscopy adverse effects, Pancreatic Fistula epidemiology, Pancreaticoduodenectomy adverse effects, Postoperative Complications epidemiology, Robotic Surgical Procedures adverse effects
- Abstract
Background: Studies evaluating the efficacy of minimally invasive approaches to pancreatoduodenectomy (MIS-PD) compared to open pancreatioduodenectomy (OPD) have been limited by selection bias and mixed outcomes., Methods: ACS-NSQIP 2014-2015 pancreas procedure-targeted data were used to identify patients undergoing PD. Intention-to-treat analysis was performed., Results: Of 7907 PD patients, 1277 (16%) underwent MIS-PD: 776 (61%) robotic or laparoscopic PD, 304 (24%) hybrid, and 197 (15%) unplanned conversions. There were no differences in demographics or comorbidities. Patients undergoing MIS-PD were less likely to have pancreatic ductal adenocarcinoma (30.9% vs 53.9%, P < 0.01) and less likely to have a dilated pancreatic duct (21.8% vs 46.7%, P < 0.01). 30-day morbidity was less for MIS-PD (63.6% vs 76.9%, P < 0.01), due to decreased delayed gastric emptying DGE) in the MIS-PD group (8.6% vs 15.5%, P < 0.01). 30-day mortality, length-of-stay, and readmissions were not significantly different. Patients undergoing MIS-PD had greater rates of CR-POPF (15.3% vs 13.0%, P = 0.03). On adjusted multivariable analysis, MIS-PD was not associated with CR-POPF (OR 1.05, 95% CI 0.87-1.26) but was associated with decreased DGE (OR 0.57, 95% CI 0.46-0.71)., Conclusion: MIS-PD has comparable short-term outcomes to open PD. While CR-POPF rates are greater for MIS-PD, this increased risk appears related to case-selection bias and not inherent to the MIS-approach., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2018
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41. Minimally Invasive Adrenalectomy for Adrenocortical Carcinoma: Five-Year Trends and Predictors of Conversion.
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Calcatera NA, Hsiung-Wang C, Suss NR, Winchester DJ, Moo-Young TA, and Prinz RA
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- Adrenalectomy trends, Adult, Aged, Conversion to Open Surgery statistics & numerical data, Female, Humans, Laparoscopy methods, Male, Margins of Excision, Middle Aged, Retrospective Studies, Risk Factors, Adrenal Cortex Neoplasms surgery, Adrenalectomy methods, Adrenocortical Carcinoma surgery, Minimally Invasive Surgical Procedures trends
- Abstract
Background: Adrenocortical carcinoma (ACC) is rare but often fatal. Surgery offers the only chance of cure. As minimally invasive (MI) procedures for cancer become common, their role for ACC is still debated. We reviewed usage of MI approaches for ACC over time and risk factors for conversion using a large national database., Methods: ACC patients with localized disease were identified in the National Cancer Data Base from 2010 to 2014. A retrospective review examined trends in the surgical approach over time. Patient demographics, surgical approach, and tumor characteristics between MI, open, and converted procedures were compared., Results: 588 patients underwent adrenalectomy for ACC, of which 200 were minimally invasive. From 2010 to 2014, MI operations increased from 26 to 44% with robotic procedures increasing from 5 to 16%. The use of MI operations compared to open was not different based on facility type (p = 0.40) or location (p = 0.63). MI tumors were more likely to be confined to the adrenal (p < 0.001) but final margin status was not different (p = 0.56). Conversion was performed in 38/200 (19%). Average tumor size was 10.2 cm in the converted group compared to 8.6 cm in the MI group (p = 0.09). There was no difference in extent of disease (p = 0.33), margin status (p = 0.12), or lymphovascular invasion (p = 0.59) between MI and converted procedures. Tumor size > 5 cm was the only significant predictor of conversion (p = 0.04). No patients with pathologic stage I disease required conversion (0/19)., Conclusions: The frequency of MI approaches for ACC is increasing. In the final year of the study, 44% of adrenalectomies were MI. Size > 5 cm was the only significant predictor of conversion.
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- 2018
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42. The extent of vascular resection is associated with perioperative outcome in patients undergoing pancreaticoduodenectomy.
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Kantor O, Talamonti MS, Wang CH, Roggin KK, Bentrem DJ, Winchester DJ, Prinz RA, and Baker MS
- Subjects
- Aged, Blood Loss, Surgical prevention & control, Blood Transfusion, Carcinoma, Pancreatic Ductal mortality, Carcinoma, Pancreatic Ductal pathology, Databases, Factual, Female, Humans, Male, Mesenteric Veins pathology, Middle Aged, Operative Time, Pancreatic Neoplasms mortality, Pancreatic Neoplasms pathology, Postoperative Hemorrhage etiology, Postoperative Hemorrhage surgery, Reoperation, Retrospective Studies, Risk Assessment, Risk Factors, Shock, Septic etiology, Time Factors, Treatment Outcome, United States, Vascular Surgical Procedures adverse effects, Vascular Surgical Procedures mortality, Carcinoma, Pancreatic Ductal surgery, Mesenteric Veins surgery, Pancreatic Neoplasms surgery, Pancreaticoduodenectomy adverse effects, Pancreaticoduodenectomy mortality, Vascular Surgical Procedures methods
- Abstract
Background: Few studies have examined the relation between extent of vascular resection and morbidity following pancreaticoduodenectomy (PD) with vein resection (PDVR)., Methods: Patients undergoing PD for malignancy were identified using the American College of Surgeons National Surgical Quality Improvement Project from 2006 to 2013. Current procedural terminology codes were used to characterize PDVR., Results: 9235 patients underwent PD, 977 (10.6%) had PDVR - 640 with direct and 224 with graft repair. PDVR had longer operative times (456 ± 136 vs 374 ± 128 min, p < 0.05) and higher intraoperative transfusions (1.8 ± 3.4 vs 4.3 ± 4.9 units, p < 0.05) than PD alone. On adjusted multivariable regression, PDVR with either direct or graft repairs was associated with higher rates of overall morbidity (OR [odds ratio] 1.50 for direct, 1.74 for graft, p < 0.05), bleeding (OR 2.18 for direct, 3.26 for graft, p < 0.05), and DVT (OR 2.12 for direct, 2.62 for graft, p < 0.05) compared to PD alone. Graft repair was further associated with increased risk of reoperation (OR 1.59), septic shock (OR 2.77) and 30-day mortality (OR 2.72), all p < 0.05., Discussion: The risk of significant morbidity and mortality for PDVR is associated with the extent of vascular resection, with graft repairs having increased morbidity and mortality rates., (Copyright © 2017. Published by Elsevier Ltd.)
- Published
- 2018
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43. CONCORDANCE OF PRE-OPERATIVE CLINICAL STAGE WITH PATHOLOGIC STAGE IN PATIENTS ≥45 YEARS OLD WITH WELL-DIFFERENTIATED THYROID CANCER.
- Author
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Calcatera NA, Lutfi W, Suman P, Suss NR, Wang CH, Prinz RA, Winchester DJ, and Moo-Young TA
- Subjects
- Adenocarcinoma, Follicular surgery, Aged, Aged, 80 and over, Carcinoma, Papillary surgery, Female, Humans, Iodine Radioisotopes therapeutic use, Logistic Models, Male, Margins of Excision, Middle Aged, Multivariate Analysis, Neck Dissection, Neoplasm Staging, Neoplasms, Multiple Primary surgery, Preoperative Period, Radiotherapy, Adjuvant, Retrospective Studies, Risk Factors, Thyroid Cancer, Papillary, Thyroid Neoplasms surgery, Thyroidectomy, Tumor Burden, Adenocarcinoma, Follicular pathology, Carcinoma, Papillary pathology, Neoplasms, Multiple Primary pathology, Thyroid Neoplasms pathology
- Abstract
Objective: Clinical stage (cStage) in thyroid cancer determines extent of surgical therapy and completeness of resection. Pathologic stage (pStage) is an important determinant of outcome. The rate of discordance between clinical and pathologic stage in thyroid cancer is unknown., Methods: The National Cancer Data Base was queried to identify 27,473 patients ≥45 years old with cStage I through IV differentiated thyroid cancer undergoing surgery from 2008-2012., Results: There were 16,286 (59.3%) cStage I patients; 4,825 (17.6%) cStage II; 4,329 (15.8%) cStage III; and 2,013 (7.3%) cStage IV patients. The upstage rate was 15.1%, and the downstage rate was 4.6%. For cStage II, there was a 25.5% upstage rate. The change in cStage was a result of inaccurate T-category in 40.8%, N-category in 36.3%, and both in 22.9%. On multivariate analysis, the patients more likely to be upstaged had papillary histology, tumors 2.1 to 4 cm, total thyroidectomy, nodal surgery, positive margins, or multifocal disease. Upstaged patients received radioiodine more frequently (75.3% vs. 48.1%; P<.001)., Conclusion: Approximately 20% of cStage is discordant to pStage. Certain populations are at risk for inaccurate staging, including cT2 and cN0 patients. Upstaged patients are more likely to receive radioactive iodine therapy., Abbreviations: CI = confidence interval; cStage = clinical stage; DTC = differentiated thyroid cancer; NCDB = National Cancer Data Base; OR = odds ratio; pStage = pathologic stage; RAI = radioactive iodine.
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- 2018
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44. Sonic Hedgehog Signaling in Thyroid Cancer.
- Author
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Xu X, Lu Y, Li Y, and Prinz RA
- Abstract
Thyroid cancer is the most common malignancy of the endocrine system. The initiation of thyroid cancer is often triggered by a genetic mutation in the phosphortidylinositol-3 kinase (PI3K) or mitogen-activated protein kinase (MAPK) pathway, such as RAS and BRAF , or by the rearrangement of growth factor receptor tyrosine kinase genes such as RET/PTC . The sonic hedgehog (Shh) pathway is evolutionarily conserved and plays an important role in the embryonic development of normal tissues and organs. Gene mutations in the Shh pathway are involved in basal cell carcinomas (BCC). Activation of the Shh pathway due to overexpression of the genes encoding the components of this pathway stimulates the growth and spread of a wide range of cancer types. The Shh pathway also plays an important role in cancer stem cell (CSC) self-renewal. GDC-0449 and LDE-225, two inhibitors of this pathway, have been approved for treating BCC and are being tested as a single agent or in combination with other drugs for treating various other cancers. Here, we review the recent findings on activation of the Shh pathway in thyroid cancer and its role in maintaining thyroid CSC self-renewal. We also summarize the recent developments on crosstalk of the Shh pathway with the MAPK and PI3K oncogenic pathways, and its implications for combination therapy.
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- 2017
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45. Preoperative adrenal biopsy does not affect overall survival in adrenocortical carcinoma.
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Suman P, Calcatera N, Wang CH, Moo-Young TA, Winchester DJ, and Prinz RA
- Subjects
- Adrenal Cortex Neoplasms surgery, Adrenalectomy, Adrenocortical Carcinoma surgery, Aged, Female, Humans, Male, Middle Aged, Prognosis, Survival Rate, Adrenal Cortex Neoplasms pathology, Adrenocortical Carcinoma pathology, Biopsy
- Abstract
Background: The impact of preoperative biopsy on overall survival (OS) in adrenocortical carcinoma (ACC) is unclear. We analyzed the National Cancer Data Base (NCDB) for factors associated with preoperative adrenal biopsy and its effect on OS in ACC., Methods: The NCDB was queried from 2003 to 2012 for M0 ACC. Patients with or without preoperative biopsy were compared for factors associated with an increased rate of biopsy. Survival analysis was performed after adjusting for patient and tumor-related variables., Results: There were 1782 patients with M0 ACC of whom 332 (19%) had a preoperative biopsy. Treatment outside academic cancer centers (OR 1.36, 95% CI 1.04-1.77, P = 0.023) and male gender (OR 1.45, 95% CI 1.11-1.88, P = 0.006) were associated with an increased rate of biopsy. In patients undergoing adrenalectomy with negative margins, biopsy failed to impact OS (log-rank P = 0.225, HR 1.20, 95% CI 0.84-1.72, P = 0.306)., Conclusions: Preoperative adrenal biopsy continues to be performed for ACC with no added survival benefit. Adrenalectomy offers the best chance of survival in patients with ACC., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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46. Laparoscopic Distal Pancreatectomy for Cancer Provides Oncologic Outcomes and Overall Survival Identical to Open Distal Pancreatectomy.
- Author
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Kantor O, Bryan DS, Talamonti MS, Lutfi W, Sharpe S, Winchester DJ, Prinz RA, and Baker MS
- Subjects
- Aged, Databases, Factual, Female, Humans, Laparoscopy, Length of Stay, Male, Margins of Excision, Middle Aged, Patient Readmission, Proportional Hazards Models, Retrospective Studies, Survival Rate, Treatment Outcome, Carcinoma, Pancreatic Ductal surgery, Pancreatectomy methods, Pancreatic Neoplasms surgery
- Abstract
Background: Laparoscopic distal pancreatectomy (LDP) has been shown to provide short-term clinical outcomes similar to open distal pancreatectomy (ODP) for patients with benign tumors. Our aim was to better define oncologic outcomes and long-term survival profiles following LDP for pancreatic ductal adenocarcinoma (PDAC)., Methods: We queried the National Cancer Database to identify patients with pathologic stage I-III PDAC who underwent distal pancreatectomy between 2010 and 2013. Logistic regression was performed to examine predictors of oncologic outcomes. Cox modeling was used for survival analysis and to estimate median overall survival (OS)., Results: One thousand five hundred fifty-four patients were included in the analysis. Patients undergoing LDP and ODP demonstrated identical probabilities of an adequate lymph node sampling and 90-day mortality. Those undergoing LDP demonstrated an increased probability of margin-negative resection (OR 1.78, CI 1.25-2.52) and a decreased probability of a prolonged hospital stay (OR 0.55, CI 0.32-0.95) or readmission (OR 0.56, CI 0.33-0.95) relative to those undergoing ODP. There was no difference in OS between groups (29.6 vs. 23.8 months, p = 0.10)., Conclusion: LDP is an effective modality for managing resectable cancer in the pancreatic body and tail. LDP provides short-term oncologic outcomes and long-term OS rates identical to those for ODP while affording an accelerated recovery.
- Published
- 2017
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47. Laparoscopic pancreaticoduodenectomy for adenocarcinoma provides short-term oncologic outcomes and long-term overall survival rates similar to those for open pancreaticoduodenectomy.
- Author
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Kantor O, Talamonti MS, Sharpe S, Lutfi W, Winchester DJ, Roggin KK, Bentrem DJ, Prinz RA, and Baker MS
- Subjects
- Aged, Chemotherapy, Adjuvant, Databases, Factual, Female, Humans, Length of Stay statistics & numerical data, Male, Multivariate Analysis, Patient Readmission statistics & numerical data, Retrospective Studies, United States epidemiology, Adenocarcinoma mortality, Adenocarcinoma surgery, Laparoscopy, Pancreatic Neoplasms mortality, Pancreatic Neoplasms surgery, Pancreaticoduodenectomy methods
- Abstract
Background: The long-term efficacy of laparoscopic pancreaticoduodenectomy (LPD) relative to open pancreaticoduodenectomy (OPD) for pancreatic adenocarcinoma has not been well studied., Methods: The National Cancer Data Base was used to compare patients undergoing LPD and OPD for stage I-II pancreatic adenocarcinoma between 2010 and 2013., Results: 828 (10%) patients underwent LPD and 7385 (90%) OPD. There were no differences in tumor or demographic characteristics between groups. On multivariable analysis adjusted for hospital volume, LPD was associated with a lower rate of readmission (p < 0.01) and trends toward shorter initial length of stay (p = 0.14) and time to adjuvant chemotherapy (p = 0.11). There were no differences between patients undergoing LPD and those undergoing OP in rates of margin negative resection, number of lymph nodes examined, perioperative mortality and median overall survival (20.7 vs 20.9 months, p = 0.68)., Conclusions: For patients with localized pancreatic adenocarcinoma, LPD provides short-term oncologic and long-term overall survival outcomes identical to OPD and is associated with decreased rates of readmission and a trend towards accelerated recovery., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2017
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48. Neoadjuvant external beam radiation is associated with No benefit in overall survival for early stage pancreatic cancer.
- Author
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Lutfi W, Talamonti MS, Kantor O, Wang CH, Stocker SJ, Bentrem DJ, Roggin KK, Winchester DJ, Marsh R, Prinz RA, and Baker MS
- Subjects
- Adenocarcinoma pathology, Chemotherapy, Adjuvant statistics & numerical data, Female, Humans, Length of Stay statistics & numerical data, Lymph Nodes pathology, Male, Middle Aged, Pancreatic Neoplasms pathology, Pancreaticoduodenectomy, Propensity Score, United States epidemiology, Adenocarcinoma mortality, Adenocarcinoma therapy, Neoadjuvant Therapy, Pancreatic Neoplasms mortality, Pancreatic Neoplasms therapy, Radiotherapy, Adjuvant
- Abstract
Objective: Neoadjuvant protocols for early stage pancreatic adenocarcinoma (PDAC) frequently involve external beam radiation used in combination with systemic chemotherapy. The benefit of radiation in these protocols has not been determined., Methods: We examined patients with stage I and II PDAC within the National Cancer Data Base between 2006 and 2012. Propensity score matching was used to compare patients receiving neoadjuvant chemotherapy including radiation (NCRT) to those receiving neoadjuvant chemotherapy without radiation (NCT) prior to pancreaticoduodenectomy., Results: Prior to matching, NCRT patients had higher rates of T3 tumors (P = 0.046) and vascular abutment (P < 0.001). Propensity score matching (1:1) yielded 397 patients per group. Patients treated with NCRT were more likely to have node negative resections (P < 0.001) but had increased rates of 90-day mortality (P = 0.015) and demonstrated a trend towards shorter overall survival (P = 0.0502) than those receiving NCT., Conclusion: In early stage PDAC, the addition of radiation to NCT is often utilized with more advanced disease and is associated with higher perioperative mortality and no long-term overall survival benefit., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
49. Response to commentary on: Risk factors for central lymph node metastasis in papillary thyroid carcinoma: A National Cancer Data Base (NCDB) study.
- Author
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Suman P, Wang CH, Abadin SS, Moo-Young TA, Prinz RA, and Winchester DJ
- Subjects
- Humans, Lymph Nodes, Lymphatic Metastasis, Risk Factors, Thyroid Cancer, Papillary, Carcinoma, Papillary, Thyroid Neoplasms
- Published
- 2016
- Full Text
- View/download PDF
50. External radiation is associated with limited improvement in overall survival in resected margin-negative stage IIB pancreatic adenocarcinoma.
- Author
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Kantor O, Talamonti MS, Lutfi W, Wang CH, Winchester DJ, Marsh R, Prinz RA, and Baker MS
- Subjects
- Adenocarcinoma pathology, Aged, Chemotherapy, Adjuvant, Female, Humans, Male, Middle Aged, Neoplasm Staging, Pancreatectomy, Pancreatic Neoplasms pathology, Proportional Hazards Models, Radiotherapy, Adjuvant, Retrospective Studies, Survival Rate, United States, Adenocarcinoma mortality, Adenocarcinoma therapy, Pancreatic Neoplasms mortality, Pancreatic Neoplasms therapy
- Abstract
Background: The absolute benefit of adjuvant external beam radiation therapy after a margin-negative resection in early stage pancreatic cancer has not been determined., Methods: We queried the National Cancer Data Base for patients with pathologic stage I-II pancreatic adenocarcinoma who underwent operative resection between 2004 and 2012. Multivariate Cox regression adjusted for age, race, comorbidities, facility type, location and volume, type of pancreatectomy, and tumor grade was used to estimate stage-specific survival., Results: A total of 15,966 patients with stage I-II pancreatic adenocarcinoma underwent upfront operative therapy (no neoadjuvant treatment) and had a margin-negative resection during the study period. A total of 835 (5.2%) patients were pathologic stage IA, 1,539 (9.5%) were stage IB, 3,378 (20.9%) were stage IIA, and 10,214 (63.1%) were stage IIB. Chemoradiation utilization increased with increasing stage (22.8% in stage IA vs 39.6% in stage IIB, P < .01). Chemoradiation was more common at low-volume centers (39.0% vs 31.7% at high-volume centers, P < .01) and with younger age (43.3% of patients <70 years old compared to 25.0% ≥70 years old, P < .01). Treatment at a high-volume center was associated with decreased mortality (hazard ratio 0.80-0.89) across all stages. Age ≥70 years old (hazard ratio 1.18-1.29, P < .01) and higher grade (hazard ratio 1.68-2.69, P < .01) were associated with higher risk of mortality at all stages. Chemoradiation was associated with a benefit in median overall survival over chemotherapy alone for stage IIB disease (21.8 months vs 19.5 months, P < .01). Chemoradiation was not associated with a significant benefit in median overall survival for stage IA, IB, or IIA disease (P > .30)., Conclusion: Addition of radiation to adjuvant chemotherapy after margin-negative resection of pancreatic adenocarcinoma is associated with a limited survival benefit in patients with pathologic stage IIB disease and should be weighed against its associated risks in these patient groups., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
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