Ryan J. Ellis

Microsphere-based seamless scaffolds containing macroscopic gradients of encapsulated factors for tissue engineering.

Spatial and temporal control of bioactive signals in three-dimensional (3D) tissue engineering scaffolds is greatly desired. Coupled together, these attributes may mimic and maintain complex signal patterns, such as those observed during axonal regeneration or neovascularization. Seamless polymer constructs may provide a route to achieve spatial control of signal distribution. In this study, a novel microparticle-based scaffold fabrication technique is introduced as a method to create 3D scaffolds with spatial control over model dyes using uniform poly(D,L-lactide-co-glycolide) microspheres. Uniform microspheres were produced using the Precision Particle Fabrication technique. Scaffolds were assembled by flowing microsphere suspensions into a cylindrical glass mold, and then microspheres were physically attached to form a continuous scaffold using ethanol treatment. An ethanol soak of 1 h was found to be optimum for improved mechanical characteristics. Morphological and physical characterization of the scaffolds revealed that microsphere matrices were porous (41.1 +/- 2.1%) and well connected, and their compressive stiffness ranged from 142 to 306 kPa. Culturing chondrocytes on the scaffolds revealed the compatibility of these substrates with cell attachment and viability. In addition, bilayered, multilayered, and gradient scaffolds were fabricated, exhibiting excellent spatial control and resolution. Such novel scaffolds can serve as sustained delivery devices of heterogeneous signals in a continuous and seamless manner, and may be particularly useful in future interfacial tissue engineering investigations.

miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3.

The expression and function of miR-145 in thyroid cancer is unknown. We evaluated the expression and function of miR-145 in thyroid cancer and its potential clinical application as a biomarker. We found that the expression of miR-145 is significantly downregulated in thyroid cancer as compared with normal. Overexpression of miR-145 in thyroid cancer cell lines resulted in: decreased cell proliferation, migration, invasion, VEGF secretion, and E-cadherin expression. miR-145 overexpression also inhibited the PI3K/Akt pathway and directly targeted AKT3. In vivo, miR-145 overexpression decreased tumor growth and metastasis in a xenograft mouse model, and VEGF secretion. miR-145 inhibition in normal primary follicular thyroid cells decreased the expression of thyroid cell differentiation markers. Analysis of indeterminate fine-needle aspiration samples showed miR-145 had a 92% negative predictive value for distinguishing benign from malignant thyroid nodules. Circulating miR-145 levels were significantly higher in patients with thyroid cancer and showed a venous gradient. Serum exosome extractions revealed that miR-145 is secreted. Our findings suggest that miR-145 is a master regulator of thyroid cancer growth, mediates its effect through the PI3K/Akt pathway, is secreted by the thyroid cancer cells, and may serve as an adjunct biomarker for thyroid cancer diagnosis.

Genome-Wide Methylation Patterns in Papillary Thyroid Cancer Are Distinct Based on Histological Subtype and Tumor Genotype

CONTEXT Aberrant DNA methylation is known to be a major factor in oncogenesis and cancer progression, but effects of methylation in papillary thyroid cancer (PTC) are not well defined. OBJECTIVE The objective of the study was to identify altered methylation patterns, which may be associated with PTC disease behavior. DESIGN This study was a genome-wide methylation analysis of PTC. SETTING The study was conducted at the National Institutes of Health Clinical Center. PATIENTS PTC tissue from 51 patients were analyzed and compared with normal thyroid tissue from seven patients. INTERVENTIONS CpG methylation status was assessed using advanced genome-wide methylation bead chips. OUTCOME MEASURES Altered methylation patterns in PTC were analyzed by stage, recurrence, histological subtype of tumor, and tumor genotype. RESULTS PTC is globally hypomethylated compared with normal thyroid with 2837 differentially methylated CpG sites. The follicular variant of PTC demonstrated less differential methylation with only 569 differentially methylated CpG sites. Tumors with mutations in BRAF, RET/PTC, and RAS demonstrated a 3.6-fold increase in the number of differentially methylated sites compared with wild-type tumors. The differentially methylated genes were associated with oncological pathways including cellular movement, growth, and proliferation. CONCLUSION PTC is epigenetically distinct from the follicular variant of PTC and by gene mutation status (BRAF, RET/PTC, and RAS).

The presence of SDHB mutations should modify surgical indications for carotid body paragangliomas.

Objective:The aim of this study was to determine whether the genetic background of the disease should be incorporated into treatment decision making. Background:Carotid body paragangliomas are rare tumors that often affect patients with genetic mutations of the succinate dehydrogenase complex (SDHx). Despite growing evidence that germ line genetic mutations alter the aggressiveness of paragangliomas, treatment decisions are currently based only on clinical symptoms and tumor size in patients with carotid body paragangliomas. Methods:Retrospective analysis of 34 patients with carotid body paragangliomas who underwent genetic testing and surgical treatment. Recurrence was defined by the return of locoregional disease and/or development of distant metastases. Clinical characteristics and genetic testing results were analyzed as predictors of patient outcomes. Results:Thirty-four patients underwent 41 primary carotid body paraganglioma resections (median follow-up time of 42 months, range: 1–293). Overall survival was 91.2%. Twelve patients had germ line mutations in SDHB, 17 in SDHD, and 5 carried no known mutation. Surgical resection of larger tumors was associated with higher operative complications (odds ratio: 5.4, P = 0.05). Tumor size at resection was significantly smaller in patients with SDHB mutations than in patients with non-SDHB mutations (2.1 vs 3.3 cm, P = 0.02). Patients with a mutation in the SDHB gene also had significantly worse disease-free survival compared with patients without an SDHB gene mutation (P = 0.03). Conclusions:Mutations in the SDHB gene are associated with worse disease-free survival after resection in patients with carotid body paragangliomas despite earlier intervention. This suggests that a more aggressive surgical approach is warranted in patients with SDHB mutations.

Hyperparathyroidism-jaw tumor syndrome: Results of operative management.

BACKGROUND Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare, autosomal-dominant disease secondary to germline-inactivating mutations of the tumor suppressor gene HRPT2/CDC73. The aim of the present study was to determine the optimal operative approach to parathyroid disease in patients with HPT-JT. METHODS A retrospective analysis of clinical and genetic features, parathyroid operative outcomes, and disease outcomes in 7 unrelated HPT-JT families. RESULTS Seven families had 5 distinct germline HRPT2/CDC73 mutations. Sixteen affected family members (median age, 30.7 years) were diagnosed with primary hyperparathyroidism (PHPT). Fifteen of the 16 patients underwent preoperative tumor localization studies and uncomplicated bilateral neck exploration at initial operation; all were in biochemical remission at most recent follow-up. Of these patients, 31% had multiglandular involvement; 37.5% of the patients developed parathyroid carcinoma (median overall survival, 8.9 years; median follow-up, 7.4 years). Long-term follow-up showed that 20% of patients had recurrent PHPT. CONCLUSION Given the high risk of malignancy and multiglandular involvement in our cohort, we recommend bilateral neck exploration and en bloc resection of parathyroid tumors suspicious for cancer and life-long postoperative follow-up.

Response after Surgical Resection of Metastatic Pheochromocytoma and Paraganglioma: Can Postoperative Biochemical Remission Be Predicted?

BACKGROUND Aggressive surgical resection with intent to cure and surgical debulking procedures are commonly recommended in patients with metastatic pheochromocytoma and paraganglioma. To date there are no data on operative outcomes of patients after surgical resection of metastatic pheochromocytoma and paraganglioma to determine if such an approach is appropriate and what factors may be associated with a favorable outcome. STUDY DESIGN We performed a retrospective analysis of 30 patients with metastatic pheochromocytoma/paraganglioma who underwent surgical treatment. Clinical characteristics and genetic factors were analyzed as predictors of biochemical response to surgery. RESULTS Thirty patients underwent a total of 42 operations, with a median follow-up time of 24 months (range 1 to 114 months). Complete disease resection (R0/R1) was achieved in 18 (42.9%) cases; 24 cases (57.1%) were debulking (R2) procedures without intent to cure. Complete biochemical remission was achieved in 10 (23.8%) cases and partial biochemical response was achieved in 23 (54.8%) cases. Patients with disease confined to the abdomen were more likely to achieve and maintain a biochemical response postoperatively than those with extra-abdominal disease (p = 0.0003). Debulking operations were significantly less likely to achieve or maintain biochemical palliation, with only 1 patient maintaining a biochemical response 12 months postoperatively (p < 0.0001). Patients were less likely to obtain pharmacologic independence after debulking (p = 0.0003), with only 2 (8.3%) not requiring pharmacotherapy 6 months after the intervention. Factors not associated with biochemical response to surgery include sex, family history, SDHB mutation status, systemic therapy, and preoperative biochemical profile. CONCLUSIONS Depending on the extent of disease, patients with metastatic pheochromocytoma/paraganglioma can benefit from aggressive operative intervention and resection with intent to cure. Debulking procedures are unlikely to achieve clinically significant biochemical response, with any biochemical response achieved being very short-lived.

Prospective Evaluation of the Clinical Utility of 18-Fluorodeoxyglucose PET CT Scanning in Patients with Von Hippel-Lindau–Associated Pancreatic Lesions

BACKGROUND The natural history of pancreatic neuroendocrine neoplasms (PNENs) in patients with Von Hippel-Lindau (VHL) disease is poorly defined. Management of patients with PNENs is challenging because there are no reliable preoperative criteria to detect malignant lesions, and the majority of resected tumors are found to be benign. The aim of this study was to determine whether 18-fluorodeoxyglucose-positron emission tomography ((18)FDG-PET) uptake predicts growth and detects malignant VHL-associated PNENs. STUDY DESIGN We performed a prospective study of 197 patients with VHL-associated pancreatic lesions. Clinical and imaging characteristics were analyzed to study the associations between FDG-PET uptake, tumor growth, and the development of metastatic disease. RESULTS One hundred nine of 197 patients had solid pancreatic lesions and underwent both CT and (18)FDG-PET scanning, which identified 165 and 144 lesions, respectively. Metastatic disease was detected by (18)FDG-PET in 3 patients in whom it was not detected by CT scan and suggested non-neoplastic disease in 3 patients. Maximum standardized uptake values (SUV) on (18)FDG-PET correlated with tumor size on CT (r = 0.47, p < 0.0001), and an increase in SUVmax was associated with tumor growth (r = 0.36, p = 0.0062). No association was seen between (18)FDG-PET uptake and age, VHL genotype, or serum chromogranin A levels. CONCLUSIONS Scanning with FDG-PET identifies metastatic disease not detected by CT scan and avoids resection of non-PNEN lesions that have no malignant potential in patients with VHL-associated PNENs. It should be considered as a valuable functional imaging modality in the clinical management of patients with VHL-associated PNENs.

Databases for surgical health services research: American College of Surgeons National Surgical Quality Improvement Program

h 0 The impetus for the creation of the American College of Sureons National Surgical Quality Improvement Program (ACS NSQIP) an be traced back to the creation of the Veterans Affairs NSQIP VA NSQIP) in the 1990s. Anecdotal evidence at the time seemed o indicate that the operative mortality within the VA system was reater than the national average, and subsequent legislation manated that VA hospitals compare risk-adjusted surgical outcomes o the national average. 1 Three nonfederal hospitals joined the VA NSQIP program n 1999, demonstrating that rigorous data collection and riskdjustment methods have broader applicability in surgical qualty research. The ACS subsequently conducted the Patient Safety n Surgery Study, which reduced morbidity and mortality in paricipating hospitals by utilizing VA NSQIP methodology to idenify process shortcomings outside the VA setting. 2 ACS NSQIP was reated in 2004 and began enrolling new private sector hospitals. here has been significant growth during the intervening years, nd the database includes > 5.5 million cases with > 990,0 0 0 new ases in 2016 ( Fig 1 ).

Databases for surgical health services research: National cancer database

There has been growing attention to quality measurement in urgical oncology. The 1999 landmark publication “To Err is Huan” by the Institute of Medicine brought widespread awareness o deficiencies in patient safety. 1 In the same year, the Institute of edicine reported substantial variation in quality of cancer care in Ensuring Quality Cancer Care.”2 In the ensuing decades, the Naional Quality Forum launched a program to encourage developent of cancer-specific quality measures and, in 2007, endorsed quality measures developed in a joint effort between the Amerian College of Surgeons Commission on Cancer (ACS CoC), National omprehensive Cancer Network, and American Society of Clinical ncology. The Affordable Care Act subsequently included a clear andate for performance evaluation, including a requirement of ancer care performance assessment. However, development of quality metrics is only one step toard quality improvement. Achieving and sustaining high-quality ncology care also depend on accurate clinical data to assess these easures and robust feedback mechanisms to facilitate practice hanges at the frontline of care delivery. The National Cancer atabase (NCDB) is one such tool that has had a tremendous efect on cancer care in the United States.

Improving the quality of surgical care: The American College of Surgeons National Surgical Quality Improvement Program

a Division of Research and Optimal Patient Care, American College of Surgeons, Chicago, IL, United States b Surgical Outcomes and Quality Improvement Center (SOQIC), Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States c Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA, United States d VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States