Publications by authors named "Christopher D Raeburn"

42 Publications

Melanoma Metastases to the Adrenal Gland Are Highly Resistant to Immune Checkpoint Inhibitors.

J Natl Compr Canc Netw 2021 Aug 4. Epub 2021 Aug 4.

3Center for Rare Melanomas.

Background: Adrenal gland metastases (AGMs) are common in advanced-stage melanoma, occurring in up to 50% of patients. The introduction of immune checkpoint inhibitors (ICIs) has markedly altered the outcome of patients with melanoma. However, despite significant successes, anecdotal evidence has suggested that treatment responses in AGMs are significantly lower than in other metastatic sites. We sought to investigate whether having an AGM is associated with altered outcomes and whether ICI responses are dampened in the adrenal glands.

Patients And Methods: We retrospectively compared ICI responses and overall survival (OS) in 68 patients with melanoma who were diagnosed with an AGM and a control group of 100 patients without AGMs at a single institution. Response was determined using RECIST 1.1. OS was calculated from time of ICI initiation, anti-PD-1 initiation, initial melanoma diagnosis, and stage IV disease diagnosis. Tumor-infiltrating immune cells were characterized in 9 resected AGMs using immunohistochemical analysis.

Results: Response rates of AGMs were significantly lower compared with other metastatic sites in patients with AGMs (16% vs 22%) and compared with those without AGMs (55%). Patients with AGMs also had significantly lower median OS compared with those without AGMs (3.1 years vs not reached, respectively). We further observed that despite this, AGMs exhibited high levels of tumor-infiltrating immune cells.

Conclusions: In this cohort of patients with melanoma, those diagnosed with an AGM had lower ICI response rates and OS. These results suggest that tissue-specific microenvironments of AGMs present unique challenges that may require novel, adrenal gland-directed therapies or surgical resection.
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http://dx.doi.org/10.6004/jnccn.2020.7800DOI Listing
August 2021

Mastermind Like Transcriptional Coactivator 3 (MAML3) Drives Neuroendocrine Tumor Progression.

Mol Cancer Res 2021 09 13;19(9):1476-1485. Epub 2021 May 13.

Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado, Aurora, Colorado.

Metastatic disease in pheochromocytomas and paragangliomas (PCC/PGL) is not well-understood. The Cancer Genome Atlas discovered recurrent fusion genes in a subset of tumors that lacked known germline or somatic driver mutations and were associated with aggressive disease. Here, we aimed to investigate the role of MAML3 in tumorigenesis. Human PCC/PGLs were used for IHC and genetic analysis. Three neuroendocrine tumor cell lines, SK-N-SH, QGP-1, and BON-1, were transiently transfected with (FL) or exon 1 deleted (dEx1; mimicking the fusion), and biologic effects of overexpression were examined . We found 7% (4/55) of human PCC/PGL have fusions and all were sporadic cases with metastatic disease. Fusion-positive tumors had intense MAML3 nuclear staining and increased β-catenin by IHC and showed increased expression. , overexpression of FL and dEx1 MAML3 increased invasion in SK-N-SH, QGP-1, and BON-1 (all < 0.05) and increased soft-agar colony formation in QGP-1 and BON-1 (all < 0.05). Cotransfection with FL or dEx1 MAML3 and β-catenin increased TCF/LEF promoter activation by luciferase activity and coimmunoprecipitation confirmed interaction between MAML3 and β-catenin. These data suggest MAML3 is involved in WNT signaling pathway activation. In summary, fusions are present in a subset of PCC/PGL and associated with metastatic disease without other known drivers. MAML3 overexpression led to increased tumorigenicity in neuroendocrine tumor cells and the mechanism of action may involve WNT signaling pathways. IMPLICATIONS: MAML3 increases tumorigenicity and invasion in neuroendocrine tumor cells and may be a prognostic marker for aggressive disease.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419063PMC
September 2021

Inhibition of BRAF and ERK1/2 has synergistic effects on thyroid cancer growth in vitro and in vivo.

Mol Carcinog 2021 03;60(3):201-212

Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Mutations in the BRAF gene are highly prevalent in thyroid cancer. However, the response rate of thyroid tumors to BRAF-directed therapies has been mixed. Increasingly, combination therapies inhibiting the MAPK pathway at multiple nodes have shown promise. Recently developed ERK1/2 inhibitors are of interest for use in combination therapies as they have the advantage of inhibiting the most downstream node of the MAPK pathway, therefore preventing pathway reactivation. Here, we examined the effect of combined BRAF inhibition (dabrafenib) and ERK1/2 inhibition (SCH772984) on the growth and survival of a panel of BRAF-mutant thyroid cancer cell lines using in vitro and in vivo approaches. We found that resistance due to MAPK pathway reactivation occurs quickly with single-agent BRAF inhibition, but can be prevented with combined BRAF and ERK1/2 inhibition. Combined inhibition also results in synergistic growth inhibition, decreased clonogenic survival, and enhanced induction of apoptosis in a subset of BRAF-mutant thyroid cancer cells. Finally, combined inhibition of BRAF and ERK1/2 results in enhanced inhibition of tumor growth in an anaplastic thyroid cancer in vivo model. These results provide key rationale to pursue combined BRAF and ERK1/2 inhibition as an alternative therapeutic strategy for BRAF-mutant advanced thyroid cancer patients.
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http://dx.doi.org/10.1002/mc.23284DOI Listing
March 2021

Leptomeningeal Metastasis from Adrenocortical Carcinoma: A Case Report.

J Endocr Soc 2020 Mar 12;4(3):bvaa017. Epub 2020 Feb 12.

Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado, Aurora, Colorado.

Adrenocortical carcinoma (ACC) is an uncommon endocrine malignancy with limited treatment options. While the overall 5-year survival rate in patients with ACC is 35%, the disease is often rapidly progressive with long-term survival in only 5% of patients. Although tumor stage, grade, and excess hormonal activity predict unfavorable prognosis, additional biomarkers are needed to identify patients with aggressive disease. A 23-year-old woman presented with rapidly progressing signs and symptoms of Cushing's syndrome, with associated abdominal pain and fullness. Evaluation revealed a large left adrenal mass which had developed over 8 months. En bloc surgical resection was performed by an endocrine surgeon, and pathology revealed adrenocortical carcinoma with Ki67 of 60%. Despite adjuvant treatment with mitotane and etoposide-doxorubicin-carboplatin chemotherapy, the patient had rapid disease progression with metastatic spread to liver, lung, bone, brain, and leptomeningies, and she died 11 months after the initial diagnosis. Subsequent analysis of the patient's tumor revealed mutations in and . RNA sequencing was compared against the the Cancer Genome Atlas data set and clustered with the high steroid, proliferative subtype, associated with the worst prognosis. The tumor also demonstrated a low ratio and G0S2 hypermethylation, both predictive of very aggressive ACC. This case represents a subset of ACC characterized by rapid and fatal progression. Clinically available predictors as well as recently reported molecular signatures and biomarkers correlated with this tumor's aggressiveness, suggesting that development and validation of combinations of biomarkers may be useful in guiding personalized approaches to patients with ACC.
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http://dx.doi.org/10.1210/jendso/bvaa017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053406PMC
March 2020

NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2018.

J Natl Compr Canc Netw 2018 12;16(12):1429-1440

The NCCN Guidelines for Thyroid Carcinoma provide recommendations for the management of different types of thyroid carcinoma, including papillary, follicular, Hürthle cell, medullary, and anaplastic carcinomas. These NCCN Guidelines Insights summarize the panel discussion behind recent updates to the guidelines, including the expanding role of molecular testing for differentiated thyroid carcinoma, implications of the new pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features, and the addition of a new targeted therapy option for V600E-mutated anaplastic thyroid carcinoma.
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http://dx.doi.org/10.6004/jnccn.2018.0089DOI Listing
December 2018

Elucidating the Role of the Maternal Embryonic Leucine Zipper Kinase in Adrenocortical Carcinoma.

Endocrinology 2018 07;159(7):2532-2544

Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, Colorado Anschutz Medical Campus, Aurora, Colorado.

Adrenocortical carcinoma (ACC) is an aggressive cancer with a 5-year survival rate <35%. Mortality remains high due to lack of targeted therapies. Using bioinformatic analyses, we identified maternal embryonic leucine zipper kinase (MELK) as 4.1-fold overexpressed in ACC compared with normal adrenal samples. High MELK expression in human tumors correlated with shorter survival and with increased expression of genes involved in cell division and growth. We investigated the functional effects of MELK inhibition using newly developed ACC cell lines with variable MELK expression, CU-ACC1 and CU-ACC2, compared with H295R cells. In vitro treatment with the MELK inhibitor, OTSSP167, resulted in a dose-dependent decrease in rates of cell proliferation, colony formation, and cell survival, with relative sensitivity of each ACC cell line based upon the level of MELK overexpression. To confirm a MELK-specific antitumorigenic effect, MELK was inhibited in H295R cells via multiple short hairpin RNAs. MELK silencing resulted in 1.9-fold decrease in proliferation, and 3- to 10-fold decrease in colony formation in soft agar and clonogenicity assays, respectively. In addition, although MELK silencing had no effect on survival in normoxia, exposure to a hypoxia resulted in a sixfold and eightfold increase in apoptosis as assessed by caspase-3 activation and TUNEL, respectively. Together these data suggest that MELK is a modulator of tumor cell growth and survival in a hypoxic microenvironment in adrenal cancer cells and support future investigation of its role as a therapeutic kinase target in patients with ACC.
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http://dx.doi.org/10.1210/en.2018-00310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669820PMC
July 2018

Development of new preclinical models to advance adrenocortical carcinoma research.

Endocr Relat Cancer 2018 04 25;25(4):437-451. Epub 2018 Jan 25.

Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA.

Adrenocortical cancer (ACC) is an orphan malignancy that results in heterogeneous clinical phenotypes and molecular genotypes. There are no curative treatments for this deadly cancer with 35% survival at five years. Our understanding of the underlying pathobiology and our ability to test novel therapeutic targets has been limited due to the lack of preclinical models. Here, we report the establishment of two new ACC cell lines and corresponding patient-derived xenograft (PDX) models. CU-ACC1 cell line and PDX were derived from a perinephric metastasis in a patient whose primary tumor secreted aldosterone. CU-ACC2 cell line and PDX were derived from a liver metastasis in a patient with Lynch syndrome. Short tandem repeat profiling confirmed consistent matches between human samples and models. Both exomic and RNA sequencing profiling were performed on the patient samples and the models, and hormonal secretion was evaluated in the new cell lines. RNA sequencing and immunohistochemistry confirmed the expression of adrenal cortex markers in the PDXs and human tumors. The new cell lines replicate two of the known genetic models of ACC. CU-ACC1 cells had a mutation in and secreted cortisol but not aldosterone. CU-ACC2 cells had a mutation and loss of consistent with the patient's known germline mutation causing Lynch syndrome. Both cell lines can be transfected and transduced with similar growth rates. These new preclinical models of ACC significantly advance the field by allowing investigation of underlying molecular mechanisms of ACC and the ability to test patient-specific therapeutic targets.
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http://dx.doi.org/10.1530/ERC-17-0447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831504PMC
April 2018

Oncocytic variant of medullary thyroid carcinoma; a rare tumor with numerous diagnostic mimics by fine needle aspiration.

Diagn Cytopathol 2017 Dec 12;45(12):1148-1152. Epub 2017 Aug 12.

Department of Pathology, University of Colorado at Denver and Health Sciences Center, Aurora, CO, 80045.

Oncocytic variant of medullary thyroid carcinoma is rare form of thyroid carcinoma that is easily misdiagnosed on fine needle aspiration specimens due to it is low incidence and cytomorphologic overlap with other more common Hurtle cell lesions. A correct initial diagnosis by fine needle aspiration is imperative as the clinical treatment for medullary carcinoma differs significantly from the mimickers. We present a case of this rare variant tumor that on initial fine needle aspiration was described as a Hurthle cell lesion and was subsequently correctly classified on the resection specimen. In this brief review, we describe the cytomorphologic features of medullary carcinoma, oncocytic variant of medullary carcinoma and it is most common mimickers, and we discuss the ancillary studies required to confirm the diagnosis. This case highlights the importance of a complete clinical history and radiologic correlation, which in conjunction with a careful attention to the cytologic features of the fine needle aspiration sample, should in most cases ensure a correct initial diagnosis.
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http://dx.doi.org/10.1002/dc.23790DOI Listing
December 2017

Tumor-Infiltrating T Cells and the PD-1 Checkpoint Pathway in Advanced Differentiated and Anaplastic Thyroid Cancer.

J Clin Endocrinol Metab 2016 07 5;101(7):2863-73. Epub 2016 Apr 5.

Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.

Context: Five to 10% of patients with differentiated thyroid cancers (DTC) develop invasive and/or distant metastatic disease that is marginally improved with standard therapies. Prognosis is poor for patients with anaplastic thyroid cancer, with a median survival of 3-5 months. We suggest that a paradigm shift is necessary in the treatment of advanced cases.

Objective: We hypothesized that a T-cell response is generated in advanced thyroid cancer and may be a viable therapeutic target.

Design: Primary DTCs were analyzed by quantitative RT-PCR (n = 92) for expression of CD3, CD8, forkhead box (Fox)-P3, programmed death (PD)-1, PD-1 ligand-1, and PD-1 ligand-2 and biopsied for cellular analysis by flow cytometry (n = 11). Advanced pT4 cases (n = 22) and metastases (n = 5) were analyzed by immunohistochemistry.

Setting: The study was conducted at the University of Colorado Hospital.

Patients: Thyroid cancer patients undergoing thyroidectomy or completion surgery for advanced disease between 2002 and 2013 participated in the study.

Intervention: There were no interventions.

Main Outcome Measure: Immune markers were analyzed for association with disease severity.

Results: Immune markers were commonly expressed at the RNA level. PD-L1 was higher (P = .0443) in patients with nodal metastases. FoxP3(+) (P < .0001), PD-1(+)CD8(+) (P = .0058), and PD-1(+)CD4(+) (P = .0104) T cells were enriched in DTC biopsies. CD8(+) and FoxP3(+) T cells were detected by immunohistochemistry in all pT4 tumors and a subset of metastases. PD-1(+) lymphocytes were found in 50% of DTCs. PD-L1 was expressed by tumor and associated leukocytes in 13 of 22 cases, and expression was more diffuse in anaplastic thyroid cancer (P = .0373). BRAF(V600E) mutation was associated with higher frequencies of tumor-associated lymphocytes (P = .0095) but not PD-L1 expression.

Conclusions: PD-1 checkpoint blockades may have therapeutic efficacy in patients with aggressive forms of thyroid cancer.
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http://dx.doi.org/10.1210/jc.2015-4227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929840PMC
July 2016

Frequency of varicella zoster virus DNA in human adrenal glands.

J Neurovirol 2016 06 3;22(3):400-2. Epub 2016 Feb 3.

Department of Neurology, University of Colorado School of Medicine, 12700 E. 19th Avenue, Box B-182, Aurora, CO, 80045, USA.

Varicella zoster virus (VZV) becomes latent in ganglionic neurons derived from neural crest cells. Because the adrenal gland also contains medullary chromaffin cells of neural crest origin, we examined human adrenal glands and medullary chromaffin cell tumors (pheochromocytomas) for VZV and herpes simplex virus type 1 (HSV-1). We found VZV, but not HSV-1, DNA in 4/63 (6 %) normal adrenal glands. No VZV transcripts or antigens were detected in the 4 VZV DNA-positive samples. No VZV or HSV-1 DNA was found in 21 pheochromocytomas.
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http://dx.doi.org/10.1007/s13365-016-0425-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654543PMC
June 2016

A "safe and effective" protocol for management of post-thyroidectomy hypocalcemia.

Am J Surg 2015 Dec 26;210(6):1162-8; discussion 1168-9. Epub 2015 Sep 26.

Division of GI, Tumor and Endocrine Surgery, Department of Surgery, University of Colorado School of Medicine, Mail Stop C313, 12361 East 17th Place, Room 6001, Aurora, CO 80045, USA.

Background: This study evaluates the outcomes of a protocol to manage hypocalcemia after thyroidectomy (TTX).

Methods: A review of prospectively collected data was performed in 130 patients who underwent TTX after the introduction of a specific protocol. These patients were compared with a control group of 195 patients who underwent TTX the year prior when routine calcium supplementation was utilized and no specific protocol was used.

Results: Of the 120 patients in whom the protocol was followed, 44 (37%) patients were classified as high risk, 15 (13%) intermediate risk, and 61 (51%) low risk. The protocol had a sensitivity of 85% and a negative predictive value of 92% for predicting subsequent hypocalcemia. With the implementation of the protocol, there was significant reduction in temporary hypocalcemia events (P = .008) and intravenous calcium drip (P = .49). Also, calcium supplementation was significantly lower in the protocol group (P ≤ .001).

Conclusions: This hypocalcemia protocol identifies patients who do not require additional supplementation and additional monitoring. At the same time, it identifies those who will benefit from supplementation after TTX.
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http://dx.doi.org/10.1016/j.amjsurg.2015.07.010DOI Listing
December 2015

Parathyroid Imaging with Simultaneous Acquisition of 99mTc-Sestamibi and 123I: The Relative Merits of Pinhole Collimation and SPECT/CT.

J Nucl Med Technol 2015 Dec 19;43(4):275-81. Epub 2015 Nov 19.

Division of Nuclear Medicine, Department of Radiology, University of Colorado School of Medicine, Aurora, Colorado.

Unlabelled: The objective of this study was to determine the relative utility of 3 state-of-the-art parathyroid imaging protocols: single-time-point simultaneous acquisition of (99m)Tc-sestamibi and (123)I images with pinhole collimation in the anterior and bilateral anterior oblique projections, single-time-point simultaneous acquisition of (99m)Tc-sestamibi and (123)I images with SPECT/CT, and the combination of the first and second protocols.

Methods: Fifty-nine patients with surgical proof of parathyroid adenomas were evaluated retrospectively. All 3 protocols included perfectly coregistered subtraction images created by subtracting the (123)I images from the (99m)Tc-sestamibi images, plus an anterior parallel-hole collimator image of the neck and upper chest. The pinhole protocol was performed first, followed by the SPECT/CT protocol. Three image sets were derived from each study in each patient according to the above protocols. Two experienced observers recorded the size, location, and degree of certainty of any identified lesion.

Results: The 59 patients had 61 adenomas. For the 2 observers combined, the localization success rate was 88% for the pinhole protocol, 69% for the SPECT/CT protocol, and 81% for the combined protocol. The pinhole protocol detected more adenomas than the SPECT/CT protocol and missed fewer adenomas than either the SPECT/CT protocol or the combined pinhole and SPECT/CT protocol (P < 0.01). The 2 protocols that included SPECT/CT provided superior anatomic information relative to the location and size of the parathyroid adenomas.

Conclusion: The pinhole protocol localized significantly more adenomas than the SPECT/CT protocol. However, the protocols that included SPECT/CT provided more anatomic information than pinhole imaging alone.
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http://dx.doi.org/10.2967/jnmt.115.164939DOI Listing
December 2015

Anaplastic Thyroid Carcinoma, Version 2.2015.

J Natl Compr Canc Netw 2015 Sep;13(9):1140-50

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986600PMC
http://dx.doi.org/10.6004/jnccn.2015.0139DOI Listing
September 2015

PD-1+Tim-3+ CD8+ T Lymphocytes Display Varied Degrees of Functional Exhaustion in Patients with Regionally Metastatic Differentiated Thyroid Cancer.

Cancer Immunol Res 2015 Jun 19;3(6):620-30. Epub 2015 Feb 19.

Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, Colorado. University of Colorado Cancer Center, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.

Regional metastatic differentiated thyroid cancer (mDTC) provides a unique model in which to study the tumor-immune interface. These lymph node metastases persist for years, generally without progression to distant metastases. Although the immune system likely impedes disease progression, it is unsuccessful in eliminating disease. Our previous studies revealed that programmed death-1 (PD-1)(+) T cells were enriched in tumor-involved lymph nodes (TILN). Tumor-associated leukocytes and tumor cells were collected from grossly involved lymph nodes from 12 patients to further characterize the phenotype and functional potential of mDTC-associated PD-1(+) T cells. PD-1(+)CD4(+) and PD-1(+)CD8(+) T cells were enriched in 8 of 12 TILN samples. PD-1(+) T cells coexpressed Tim-3 and CD69 and failed to downregulate CD27. CD8(+) T cells, but not CD4(+) T cells, from these samples were variably deficient in their ability to produce effector cytokines when compared with control TILNs that lacked resident PD-1(+) T cells. PD-1(+)CD8(+) T cells were capable of exocytosis but lacked intracellular perforin. Surprisingly, T-cell proliferative capacity was largely maintained in all samples. Thus, although PD-1 expression by mDTC-associated CD8(+) T cells was associated with dysfunction, exhaustion was not complete. Notably, molecular markers of exhaustion did not translate to dysfunction in all samples or in CD4(+) T cells. Regulatory T cells (Treg), PD-L1, and galectin-9 were commonly found in mDTC and likely contributed to the initiation of T-cell exhaustion and disease progression. Therapies that release the effects of PD-1 and Tim-3 and reduce the suppressive effects of Tregs may encourage tumor elimination in patients with mDTC.
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http://dx.doi.org/10.1158/2326-6066.CIR-14-0201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457654PMC
June 2015

Thyroid carcinoma, version 2.2014.

J Natl Compr Canc Netw 2014 Dec;12(12):1671-80; quiz 1680

From Memorial Sloan Kettering Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; University of Washington/Seattle Cancer Care Alliance; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; UCSF Helen Diller Family Comprehensive Cancer Center; Fox Chase Cancer Center; University of Michigan Comprehensive Cancer Center; UC San Diego Moores Cancer Center; Huntsman Cancer Institute at the University of Utah; Stanford Cancer Institute; City of Hope Comprehensive Cancer Center; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Roswell Park Cancer Institute; Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center; Moffitt Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; Vanderbilt-Ingram Cancer Center; University of Colorado Cancer Center; The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute; Duke Cancer Institute; The University of Texas MD Anderson Cancer Center; University of Alabama at Birmingham Comprehensive Cancer Center; Massachusetts General Hospital Cancer Center; and National Comprehensive Cancer Network.

These NCCN Guidelines Insights focus on some of the major updates to the 2014 NCCN Guidelines for Thyroid Carcinoma. Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with radioactive iodine. Sorafenib may be considered for select patients with metastatic differentiated thyroid carcinoma, whereas vandetanib or cabozantinib may be recommended for select patients with metastatic medullary thyroid carcinoma. Other kinase inhibitors may be considered for select patients with either type of thyroid carcinoma. A new section on "Principles of Kinase Inhibitor Therapy in Advanced Thyroid Cancer" was added to the NCCN Guidelines to assist with using these novel targeted agents.
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http://dx.doi.org/10.6004/jnccn.2014.0169DOI Listing
December 2014

Tryptophan supplementation and postoperative delirium--a randomized controlled trial.

J Am Geriatr Soc 2014 Sep 12;62(9):1764-71. Epub 2014 Aug 12.

Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Department of Surgery, Denver Veteran's Affairs Medical Center, Denver, Colorado.

Objectives: To determine whether the postoperative administration of tryptophan would be beneficial for elderly adults undergoing surgery who are at risk of developing postoperative delirium.

Design: Randomized, double-blind, placebo-controlled trial.

Setting: Denver Veterans Affairs Medical Center.

Participants: Individuals aged 60 and older undergoing major elective operations requiring a postoperative intensive care unit (ICU) admission (n = 325).

Intervention: L-tryptophan, 1 g orally three times a day or placebo was started after surgery and continued for up to 3 days postoperatively.

Measurements: Delirium and its motor subtypes were measured using the Confusion Assessment Method-Intensive Care Unit (CAM-ICU) and the Richmond Agitation and Sedation Scale. The primary outcome for between-group comparison was the incidence of excitatory (mixed and hyperactive) postoperative delirium. The secondary outcomes for comparison were the incidence and duration of overall postoperative delirium.

Results: The overall incidence of postoperative delirium was 39% (95% confidence interval = 34-44%) (n = 116). Seventeen percent of participants in the tryptophan group and 9% in the placebo group had excitatory delirium (P = .18), and the duration of excitatory delirium was 3.3 ± 1.7 days for tryptophan and 3.1 ± 1.9 days for placebo (P = .74). Forty percent of participants in the tryptophan group and 37% in the placebo group had overall delirium (P = .60), and the duration of overall delirium was 2.9 ± 1.8 days for tryptophan and 2.4 ± 1.6 days for placebo (P = .17).

Conclusion: Postoperative tryptophan supplementation in older adults undergoing major elective operations requiring postoperative ICU admission did not reduce the incidence or duration of postoperative excitatory delirium or overall delirium.
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http://dx.doi.org/10.1111/jgs.12972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172657PMC
September 2014

Parathyroid imaging: the importance of pinhole collimation with both single- and dual-tracer acquisition.

J Nucl Med Technol 2013 Jun 28;41(2):99-104. Epub 2013 Mar 28.

Division of Nuclear Medicine, Department of Radiology, University of Colorado School of Medicine, Aurora, CO 80113, USA.

Unlabelled: Our objective was to rigorously compare pinhole and parallel-hole collimation in an intrapatient, intrastudy design in 2 parathyroid imaging protocols: the first was dual-phase (99m)Tc-sestamibi imaging, and the second was dual-phase (99m)Tc-sestamibi plus dual-tracer ((99m)Tc-sestamibi and (123)I) simultaneous-acquisition subtraction imaging.

Methods: Thirty-three patients with 37 surgically proven nonectopic parathyroid adenomas were evaluated. Anterior pinhole and parallel-hole images of the neck were available for (99m)Tc-sestamibi at 15 min and 3 h, and for simultaneously acquired (99m)Tc-sestamibi and (123)I subtraction at 15 min, all from a single study. The images were modified so that all had a square border and so that the thyroid filled approximately three quarters of the image. The images were evaluated by 2 experienced nuclear medicine physicians who did not know the surgical results or whether the images were acquired with pinhole or parallel-hole collimation. The observers indicated the location of any identified adenoma and graded the certainty of diagnosis on a 3-point scale.

Results: The localization success rate for the 2 observers combined for the single-tracer dual-phase images was 66.2% with pinhole collimation and 43.2% with parallel-hole collimation (P < 0.0001). The localization success rate with the addition of the dual-tracer simultaneous-acquisition subtraction image was 83.8% with pinhole collimation and 62.2% with parallel-hole collimation (P = 0.0018). In addition, the degree of certainty of localization was greater with pinhole collimation with both imaging protocols (P < 0.001 in both cases).

Conclusion: In the anterior projection, pinhole collimation is superior to parallel-hole collimation for parathyroid imaging with either dual-phase (99m)Tc-sestamibi or dual-phase (99m)Tc-sestamibi plus dual-tracer ((99m)Tc-sestamibi and (123)I) simultaneous-acquisition subtraction.
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http://dx.doi.org/10.2967/jnmt.112.118208DOI Listing
June 2013

Vitamin D deficiency does not increase the rate of postoperative hypocalcemia after thyroidectomy.

Am J Surg 2012 Dec;204(6):888-93; discussion 893-4

School of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Denver, CO, USA.

Background: Hypocalcemia is a frequent complication of thyroidectomy. Although typically mild and temporary, it can lead to an increased length of stay, readmission, and in some cases be permanent. Controversy exists as to whether vitamin D deficiency (VDD) contributes to post-thyroidectomy hypocalcemia.

Methods: This is a retrospective study of 152 patients who underwent thyroidectomy. Patients with or without VDD were compared. Data were analyzed for demographics, operative procedure, calcium levels, and complications of hypocalcemia.

Results: There was no difference in the rates of biochemical or symptomatic hypocalcemia or in the need for readmission between the VDD and non-VDD groups. A multivariate analysis controlling for central neck dissection, parathyroid autotransplant, and preoperative diagnosis confirmed no association between VDD and post-thyroidectomy hypocalcemia.

Conclusions: Despite VDD being common in patients undergoing thyroidectomy, our results do not suggest that this increases the rate of hypocalcemia. Thus, preoperative evaluation/repletion of VDD is unlikely to reduce post-thyroidectomy hypocalcemia rates.
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http://dx.doi.org/10.1016/j.amjsurg.2012.10.001DOI Listing
December 2012

Programmed death-1+ T cells and regulatory T cells are enriched in tumor-involved lymph nodes and associated with aggressive features in papillary thyroid cancer.

J Clin Endocrinol Metab 2012 Jun 30;97(6):E934-43. Epub 2012 Mar 30.

University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.

Context: Recurrent metastatic lymph node (LN) disease is common in patients with papillary thyroid cancer (PTC). Novel prognostic markers may be helpful in guiding a therapeutic approach. Our previous studies revealed that immune suppression is evident in PTC and associated with more severe disease.

Objective: To characterize the immune response to metastatic PTC, we assessed CD4(+) T cell polarization in LN. In addition, we investigated the role of programmed death-1 (PD-1) and T cell exhaustion.

Design: Uninvolved (UILN) and tumor-involved lymph nodes (TILN) were sampled ex vivo by fine-needle biopsy. T cell subsets were identified by flow cytometry. In parallel, archived TILN specimens were characterized by immunofluorescence.

Setting: The study was conducted at the University of Colorado Hospital.

Patients: Data were collected on 94 LN from 19 patients with PTC undergoing neck dissection.

Main Outcome: T cell subset frequencies were compared in UILN and TILN and assessed for correlation with recurrent disease and extranodal invasion.

Results: Regulatory CD4(+) T cells (Treg) were enriched in TILN compared with UILN and further elevated in TILN from patients with recurrent disease. PD-1(+) T cells were present at high frequency in TILN and markedly enriched in TILN that showed evidence of extranodal invasion. In TILN, Treg frequency correlated with PD-1(+) T cell frequencies. Although PD-1(+) T cells produced interferon-γ, they failed to fully down-regulate CD27 and were not actively proliferating.

Conclusions: Increased Treg and PD-1(+) T cell frequencies in LN may be indicative of aggressive recurrent PTC. Future prospective studies are necessary to determine the prognostic and therapeutic value of these findings in PTC.
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http://dx.doi.org/10.1210/jc.2011-3428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387418PMC
June 2012

The computerized rounding report: implementation of a model system to support transitions of care.

J Surg Res 2012 Jan 5;172(1):11-7. Epub 2011 May 5.

Department of Surgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.

Objectives: In response to ACGME work-hour restrictions, residency programs that require continuous inpatient clinical care for educational objectives will be forced to increase the proportion of junior resident experience involved in shift work. Maintaining the balance of education over service at these levels will be a challenge, where a considerable amount of time must be spent gathering data for morning rounds and signing out patients at shift change. Patient safety is an issue with this new paradigm. We hypothesized that computerized sign-out would improve resident efficiency.

Materials And Methods: A multidisciplinary clinical team collaborated to design a computerized rounding and sign-out (CSO) program to automate collection of clinical information in addition to a brief narrative describing ongoing care issues. Residents returned a self-administered questionnaire before (n = 168) and after implementation (n = 83) examining: pre-rounding time, missed patients, handoff quality, and duty hours.

Results: Residents reported spending 11 fewer min/d pre-rounding (P = 0.006). After implementation, residents missed fewer patients on rounds (P = 0.01). A majority (70%) of responders stated that the new program helped them with duty hours.

Conclusion: The current study demonstrates the reproducibility of the University of Washington model system for rounding and sign-out at an independent site, using basic infrastructure and leadership common to all residency programs. Developing a CSO was associated with a modest reduction in pre-rounding time and fewer patients missed on rounds. Although automating resident tasks may improve workflow in an increasingly complex hospital environment, structured handoff education and other institutional changes are necessary.
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http://dx.doi.org/10.1016/j.jss.2011.04.015DOI Listing
January 2012

DITPA, a thyroid hormone analog, reduces infarct size and attenuates the inflammatory response following myocardial ischemia.

J Surg Res 2011 Dec 4;171(2):379-85. Epub 2011 May 4.

Department of Surgery, University of Colorado Denver Health Sciences Center, Aurora, Colorado 80045, USA.

Background: Thyroid hormone can have positive effects on the cardiovascular system but its therapeutic potential is limited secondary to its adverse effects. DITPA (3,5-diiodothyroproprionic acid) is a synthetic thyroid hormone analog with positive inotropic effects similar to thyroid hormone but with minimal systemic effects. DITPA has previously been shown to reduce pathologic remodeling and improve cardiac output following myocardial infarction; however, few studies have examined the role of DITPA in determining infarct size or the early inflammatory response following myocardial ischemia. We examined the role of DITPA in the acute phase following infarction.

Materials And Methods: Mice were subjected to surgical induction of myocardial infarction and were then randomized to receive daily injections of DITPA or vehicle control. After 3 d, animals were sacrificed and infarct size was determined by H and E staining. Myocardial macrophage and neutrophil accumulation was determined by immunofluorescent staining. Immunoblotting and enzyme-linked immunosorbent assay (ELISA) were used to examine the levels of intercellular adhesion molecule-1 (ICAM-1), keratinocyte-derived chemokine (KC), monocyte chemoattractant protein (MCP-1), and interleukin 6 (IL-6) in homogenates from the ischemic tissue.

Results: Compared with vehicle control, DITPA treated animals had smaller infarcts (52.1%±5.7% versus 37.3%±3.6%, P<0.05) and decreased macrophage (32±4 versus 14±1 cells/HPF, P<0.05, and neutrophil (14±2 versus 7±1 cells/HPF, P<0.05) accumulation. Myocardial ICAM-1, (2.37±0.4 versus 1.1±0.2, P<0.05), KC levels (33.32±12.4 pg/mg, versus 21.24±8.9 pg/mg, P<0.05), and IL-6 levels (112.3±78 pg/mg versus 37.3±25.9 pg/mg, P<0.05) were also reduced in the DITPA treated group, while MCP-1 levels were equivalent between groups.

Conclusions: Treatment with DITPA attenuates the acute inflammatory response and reduces myocardial infarct size. The reduction in myocardial ICAM-1, KC, and IL-6 levels in the DITPA group was associated with a decrease in macrophage and neutrophil accumulation.
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http://dx.doi.org/10.1016/j.jss.2011.04.009DOI Listing
December 2011

Motor subtypes of postoperative delirium in older adults.

Arch Surg 2011 Mar;146(3):295-300

Department of Surgery, University of Colorado at Denver School of Medicine, 12631 E 17th Ave., Aurora, CO 80045, USA.

Hypothesis: Increased knowledge about motor subtypes of delirium may aid clinicians in the management of postoperative geriatric patients.

Design: Prospective cohort study defining preoperative risk factors, outcomes, and adverse events related to motor subtypes of postoperative delirium.

Setting: Referral medical center.

Patients: Persons 50 years and older with planned postoperative intensive care unit (ICU) admission following an elective operation were recruited.

Main Outcome Measures: Before surgery, a standardized frailty assessment was performed. After surgery, delirium and its motor subtypes were measured using the validated tools of the Confusion Assessment Method-ICU and the Richmond Agitation-Sedation Scale. Statistical analysis included the univariate t and χ(2) tests and analysis of variance with post hoc analysis.

Results: Delirium occurred in 43.0% (74 of 172) of patients, representing 67.6% (50 of 74) hypoactive, 31.1% (23 of 74) mixed, and 1.4% (1 of 74) hyperactive motor subtypes. Compared with those having mixed delirium, patients having hypoactive delirium were older (mean [SD] age, 71 [9] vs 65 [9] years) and more anemic (mean [SD] hematocrit, 36% [8%] vs 41% [6%]) (P = .002 for both). Patients with hypoactive delirium had higher 6-month mortality (32.0% [16 of 50] vs 8.7% [2 of 23], P = .04). Delirium-related adverse events occurred in 24.3% (18 of 74) of patients with delirium; inadvertent tube or line removals occurred more frequently in the mixed group (P = .006), and sacral skin breakdown was more common in the hypoactive group (P = .002).

Conclusions: Motor subtypes of delirium alert clinicians to differing prognosis and adverse event profiles in postoperative geriatric patients. Hypoactive delirium is the most common motor subtype and is associated with worse prognosis (6-month mortality, 1 in 3 patients). Knowledge of differing adverse event profiles can modify clinicians' management of older patients with postoperative delirium.
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http://dx.doi.org/10.1001/archsurg.2011.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346288PMC
March 2011

Extracellular heat shock cognate protein 70 induces cardiac functional tolerance to endotoxin: differential effect on TNF-alpha and ICAM-1 levels in heart tissue.

Cytokine 2010 Jul 15;51(1):60-6. Epub 2010 May 15.

Department of Surgery, University of Colorado Denver, Aurora, CO 80045, USA.

Endotoxin provokes cardiac dysfunction, and induction of tolerance to endotoxin has therapeutic potential. Heat shock protein 70 (HSP70) can induce endotoxin tolerance in macrophages. We recently found that heat shock cognate protein 70 (HSC70) induces pro-inflammatory cytokines via activation of TLR4 in macrophages and the myocardium. We hypothesize that HSC70 preconditioning induces cardiac tolerance to endotoxin. Pretreatment of peritoneal macrophages with HSC70 for 24h reduced TNF-alpha levels following endotoxin stimulation. Preconditioning of mice with HSC70 24h prior to endotoxin attenuated endotoxemic cardiac dysfunction. HSC70 preconditioning reduced TNF-alpha levels in plasma and heart tissue by 33.3% and 35.4%, respectively, and decreased ICAM-1 levels in heart tissue by 63.5% following endotoxin challenge. The effect of HSC70 on TNF-alpha was less robust than endotoxin preconditioning (79.7% and 75.0% reduction in TNF-alpha levels in plasma and heart tissue, respectively); however, HSC70 and endotoxin preconditioning had comparable effects on ICAM-1 levels in heart tissue. While HSC70 preconditioning had no effect on myocardial TLR4 protein levels, it suppressed NF-kappaB activation induced by endotoxin. We conclude that HSC70 preconditioning (1) attenuates the TNF-alpha response to endotoxin in macrophages in vitro, (2) induces cardiac functional tolerance to endotoxin and (3) reduces NF-kappaB activity, and TNF-alpha and ICAM-1 levels in heart tissue. Thus, the mechanism of HSC70-induced cardiac tolerance to endotoxin appears to involve down-regulation of myocardial TLR4 signaling and inflammatory responses.
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http://dx.doi.org/10.1016/j.cyto.2010.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905144PMC
July 2010

Postoperative delirium in the elderly: risk factors and outcomes.

Ann Surg 2009 Jan;249(1):173-8

Department of Surgery, University of Colorado at Denver School of Medicine, Denver, CO, USA.

Objective: The purpose of this study was to describe the natural history, identify risk factors, and determine outcomes for the development of postoperative delirium in the elderly.

Background: Postoperative delirium is a common and deleterious complication in geriatric patients.

Methods: Subjects older than 50 years scheduled for an operation requiring a postoperative intensive care unit admission were recruited. After preoperative informed written consent, enrolled subjects had baseline cognitive and functional assessments. Postoperatively, subjects were assessed daily for delirium using the confusion assessment method-intensive care unit. Patients were also followed for outcomes.

Results: During the study period, 144 patients were enrolled before major abdominal (40%), thoracic (53%), or vascular (7%) operations. The overall incidence of delirium was 44% (64/144). The average time to onset of delirium was 2.1 +/- 0.9 days and the mean duration of delirium was 4.0 +/- 5.1 days. Several preoperative variables were associated with an increased risk of delirium including older age (P < 0.001), hypoalbuminemia (P < 0.001), impaired functional status (P < 0.001), pre-existing dementia (P < 0.001), and pre-existing comorbidities (P < 0.001). In a multivariable logistic regression model, pre-existing dementia remains the strongest risk factor for the development of postoperative delirium. Worse outcomes, including increased length of stay (P < 0.001), postdischarge institutionalization (P < 0.001), and 6 month mortality (P = 0.001), occurred in subjects who developed delirium.

Conclusions: In the current study, delirium occurred in 44% of elderly patients after a major operation. Pre-existing cognitive dysfunction was the strongest predictor of the development of postoperative delirium. Outcomes, including an increased rate of 6 month mortality, were worse in patients who developed postoperative delirium.
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http://dx.doi.org/10.1097/SLA.0b013e31818e4776DOI Listing
January 2009

Management of duodenal and pancreaticobiliary perforations associated with periampullary endoscopic procedures.

Am J Surg 2008 Dec;196(6):975-81; discussion 981-2

Department of Surgery, University of Colorado, Denver Health Sciences Center, 12631 E 17th Avenue, C-313, PO Box 6511, Aurora, CO 80045, USA.

Background: The purpose of this study was to determine the incidence and outcome of pancreaticobiliary and duodenal (PB/D) perforations from periampullary endoscopic procedures and to examine whether clinical indexes are predictive of the need for operative management.

Methods: A retrospective review compared patients who had operative intervention for PB/D perforation with those managed nonoperatively.

Results: Thirty-two PB/D perforations occurred in 4,919 procedures (.6%). Twelve (37%) required operation; 20 (63%) were successfully managed nonoperatively. Radiographic imaging was not helpful in predicting the need for operation. A clinical scoring system was predictive of the need for operative management. The length of stay and morbidity rates were higher in the operatively managed patients.

Conclusions: Most endoscopic PB/D perforations can be successfully managed without operation and, clinical indices are most predictive in determining the need for surgery. Further prospective evaluation of this scoring system may help guide the need for and timing of operative intervention for PB/D perforations.
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http://dx.doi.org/10.1016/j.amjsurg.2008.07.045DOI Listing
December 2008

Low tryptophan levels are associated with postoperative delirium in the elderly.

Am J Surg 2008 Nov 11;196(5):670-4. Epub 2008 Sep 11.

Department of Surgery, University of Colorado at Denver, Health Sciences Center, 12631 East 17th Ave., Mail Stop C313, PO Box 6511, Aurora, CO 80045, USA.

Background: Postoperative delirium is a common complication in geriatric patients. Tryptophan is an amino acid precursor to the mood-stabilizing neurotransmitters serotonin and melatonin. We hypothesized that tryptophan levels are lower in elderly subjects who develop postoperative delirium.

Methods: A prospective observational study was performed. Subjects older than 50 years undergoing surgery with an anticipated postoperative intensive care unit admission were recruited. Postoperative delirium assessment occurred daily using the Confusion Assessment Method-intensive care unit. Peripheral serum tryptophan levels were measured 2 days after surgery.

Results: Forty-nine subjects (46 men) were enrolled, with an average age of 64 +/- 7 years. The incidence of delirium was 43% (21 of 49). The average duration of delirium was 2.9 +/- 3.0 days. Tryptophan levels were lower in the subjects who developed delirium (29.9 +/- 13.3 vs 48.5 +/- 19.8 microg/mL; P = .001).

Conclusions: Lower levels of tryptophan postoperatively were associated with the development of delirium in the elderly.
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http://dx.doi.org/10.1016/j.amjsurg.2008.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2586980PMC
November 2008

Signaling for myocardial depression in hemorrhagic shock: roles of Toll-like receptor 4 and p55 TNF-alpha receptor.

Am J Physiol Regul Integr Comp Physiol 2005 Mar 28;288(3):R600-6. Epub 2004 Oct 28.

Dept. of Surgery, Box C-320, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, CO 80262, USA.

Hemorrhagic shock causes myocardial contractile depression. Although this myocardial disorder is associated with increased expression of tumor necrosis factor-alpha (TNF-alpha), the role of TNF-alpha as a myocardial depressant factor in hemorrhagic shock remains to be determined. Moreover, it is unclear which TNF-alpha receptor mediates the myocardial depressive effects of TNF-alpha. Toll-like receptor 4 (TLR4) regulates cellular expression of proinflammatory mediators following lipopolysaccharide stimulation and may be involved in the tissue inflammatory response to injury. The contribution of TLR4 signaling to tissue TNF-alpha response to hemorrhagic shock and TLR4's role in myocardial depression during hemorrhagic shock are presently unknown. We examined the relationship of TNF-alpha production to myocardial depression in a mouse model of nonresuscitated hemorrhagic shock, assessed the influence of TLR4 mutation, resulting in defective signaling, on TNF-alpha production and myocardial depression, and determined the roles of TNF-alpha and TNF-alpha receptors in myocardial depression using a gene knockout (KO) approach. Hemorrhagic shock resulted in increased plasma and myocardial TNF-alpha (4.9- and 4.5-fold, respectively) at 30 min and induced myocardial contractile depression at 4 h. TLR4 mutation abolished the TNF-alpha response and attenuated myocardial depression (left ventricular developed pressure of 43.0 +/- 6.2 mmHg in TLR4 mutant vs. 30.0 +/- 3.6 mmHg in wild type, P < 0.05). TNF-alpha KO also attenuated myocardial depression in hemorrhagic shock, and the p55 receptor KO, but not the p75 receptor KO, mimicked the effect of TNF-alpha KO. The results suggest that TLR4 plays a novel role in signaling to the TNF-alpha response during hemorrhagic shock and that TNF-alpha through the p55 receptor activates a pathway leading to myocardial depression. Thus TLR4 and the p55 TNF-alpha receptor represent therapeutic targets for preservation of cardiac mechanical function during hemorrhagic shock.
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http://dx.doi.org/10.1152/ajpregu.00182.2004DOI Listing
March 2005

Interleukin-10 attenuates the response to vascular injury.

J Surg Res 2004 Oct;121(2):206-13

Department of Surgery, University of Colorado Health, Sciences Center, Denver, Colorado, USA.

Background: The inflammatory response to vascular injury is characterized by expression of cytokines, growth factors, and chemokines that conspire to promote vessel remodeling and intimal hyperplasia (IH). Interleukin-10 (IL-10) is a multifunctional cytokine that has several anti-inflammatory properties in vitro. Few studies have evaluated the effects of IL-10 in experimental atherosclerosis. The purpose of the present study was to determine the influence of IL-10 on vascular inflammation and IH following mechanical injury.

Methods: Wire carotid injury was performed in wild-type (WT) mice with and without IL-10 treatment. Immunohistochemistry, PCR, and ELISA assays were used to examine vessel production of basic fibroblast growth factor (bFGF), monocyte chemotactic protein-1 (MCP-1), and nuclear factor kappa B (NFkappaB). Vessels were morphometrically analyzed for IH.

Results: Carotid injury induced early expression of MCP-1 and bFGF that was abrogated in mice treated with IL-10. Similarly, injury-induced expression of NFkappaB message and protein was attenuated in mice receiving exogenous IL-10. Compared to untreated mice, IL-10 markedly decreased levels of IH. Interestingly, carotid injury in IL-10-deficient mice resulted in an augmented IH response compared to injured WT mice.

Conclusions: In an in vivo model of direct vascular injury, IL-10 decreased expression of the pro-inflammatory transcription factor, NFkappaB, and the mitogenic chemokine and growth factor, MCP-1 and bFGF, respectively. These observations were associated with IL-10-induced attenuation of IH. Furthermore, endogenous IL-10 appeared to suppress the injury response. In conclusion, exogenously delivered IL-10 may represent a clinically relevant anti-inflammatory strategy for post-injury intimal hyperplasia.
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http://dx.doi.org/10.1016/j.jss.2004.03.025DOI Listing
October 2004

Insulinoma: identification by EUS and intraoperative US.

Gastrointest Endosc 2003 Oct;58(4):575-6

University of Colorado Health Sciences Center, Denver, Colorado, USA.

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http://dx.doi.org/10.1016/s0016-5107(03)01973-4DOI Listing
October 2003

[A low level of TNF-mediates hemorrhage-induced acute lung injury via p55 TNF receptor].

Zhonghua Yi Xue Za Zhi 2003 Apr;83(8):691-4

Department of Respiratory Medicine, Nanjing General Hospital of PLA, Nanjing 210002, China.

Objective: To examine the temporal relationship of pulmonary TNF-alpha production to acute lung injury (ALI) during hemorrhagic shock (HS).

Methods: HS was induced in mice by removal of 30% of calculated total blood volume. Lung TNF-alpha was measured by ELISA. Lung neutrophil accumulation was detected by immunofluorescent staining, and pulmonary microvascular permeability was assessed using Evans blue dye.

Results: While HS induced a slight and transient increase in lung TNF-alpha, neutrophil accumulation preceded the change in lung TNF-alpha. However, lung neutrophil accumulation and the increase in microvascular permeability were abrogated in TNF-alpha knockout mice, and both were restored by administration of low dose TNF-alpha to TNF-alpha knockout mice prior to HS. Both neutrophil accumulation and microvascular leak were abrogated in p55 TNF-alpha receptor knockout mice, while p75 TNF-alpha receptor knockout mice behaved similar to wild type.

Conclusion: A low level of pulmonary TNF-alpha is sufficient to mediate HS-induced acute lung injury and that the p55 TNF-alpha receptor plays a dominant role in regulating the pulmonary inflammatory response to HS. The results suggest that anti-TNF-alpha strategies for the control of the pulmonary inflammatory response to HS can be directed toward antagonizing the p55 TNF-alpha receptor.
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April 2003
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