Publications by authors named "Diana M Cardona"

79 Publications

Extent of tumor fibrosis/hyalinization and infarction following neoadjuvant radiation therapy is associated with improved survival in patients with soft-tissue sarcoma.

Cancer Med 2022 01 27;11(1):194-206. Epub 2021 Nov 27.

Department of Orthopaedics, Duke University, Durham, North Carolina, USA.

Introduction: Current standard of care for most intermediate and high-grade soft-tissue sarcomas (STS) includes limb-preserving surgical resection with either neoadjuvant radiation therapy (NRT) or adjuvant radiation therapy. To date, there have been a few studies that attempt to correlate histopathologic response to NRT with oncologic outcomes in patients with STS.

Methods: Using our institutional database, we identified 58 patients who received NRT followed by surgical resection for primary intermediate or high-grade STS and 34 patients who received surgical resection without NRT but did receive adjuvant radiation therapy or did not receive any radiation therapy. We analyzed four histologic parameters of response to therapy: residual viable tumor, fibrosis/hyalinization, necrosis, and infarction (each ratiometrically determined). Data were stratified into two binary groups. Unadjusted, 5- and 10-year overall survival, and relapsed-free survival (RFS) were calculated using the Kaplan-Meier method.

Results: Analysis of pathologic characteristics showed that patients treated with NRT demonstrate significantly higher tumor infarction, higher tumor fibrosis/hyalinization, and a lower percent viable tumor compared with patients not treated with NRT (p < 0.0001). Based on Kaplan-Meier curve analysis and multivariate cox proportional hazard model for OS and RFS, patients treated with NRT and showing >12.5% tumor fibrosis/hyalinization have significantly higher overall survival and recurrence-free survival at 5 and 10 years.

Discussion And Conclusion: We have identified three histopathologic characteristics-fibrosis, hyalinization, and infarction-that may serve as predictive biomarkers of response to NRT for STS patients. Future prospective studies will be needed to confirm this association.
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http://dx.doi.org/10.1002/cam4.4428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704179PMC
January 2022

Histologic Analysis of Porcine Dermal Graft Augmentation in Treatment of Rotator Cuff Tears.

Am J Sports Med 2021 11 15;49(13):3680-3686. Epub 2021 Oct 15.

Department of Orthopaedic Surgery, Duke University Medical Center, Duke Sports Sciences Institute, Durham, North Carolina, USA.

Background: Biologic augmentation via extracellular matrix (ECM) scaffolds has been utilized to address rotator cuff tears with poor-quality tissue.

Purpose: To evaluate the cellular changes in graft explants taken from patients treated with porcine dermal grafts for rotator cuff tears.

Study Design: Case series; Level of evidence, 4.

Methods: Four graft biopsy specimens were obtained from patients treated with porcine dermal grafts in an interposition technique for rotator cuff tears and compared with a nonimplanted graft and a normal rotator cuff specimen. Biopsy of the graft site was performed at 18 days, 3 months, 7 months, and 10.5 months after implantation. Hematoxylin and eosin staining was used to evaluate for cellular and vascular changes. Picrosirius red (PSR) stain with 90° polarized light was performed to evaluate collagen fibril size and orientation. All biopsy specimens were analyzed by a pathologist.

Results: There was evidence of progressive remodeling of the porcine dermal grafts. The most mature grafts demonstrated vessel infiltration and extensive remodeling without evidence of inflammation, foreign body reaction, or tissue rejection. PSR demonstrated increased organization of collagen domains, resembling normal tendon by 10.5 months postoperatively.

Conclusion: This series suggests that ECM grafts may serve as an effective scaffold for host cell infiltration, collagen reorganization, and vascularization as a result of histologic changes demonstrated with retrieval of specimens from patients with rotator cuff tears that were augmented with porcine dermal grafts.
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http://dx.doi.org/10.1177/03635465211049434DOI Listing
November 2021

Immune Thrombocytopenia Associated with Hepatitis B Virus and Autoimmune Hepatitis and Recovery of Platelet Count following Liver Transplantation.

Case Rep Transplant 2021 15;2021:8484106. Epub 2021 Sep 15.

Department of Surgery, Duke University Medical Center, Durham, NC, USA.

Immune thrombocytopenia is a consumptive coagulopathy that can be either idiopathic or associated with infectious or autoimmune etiologies. Here, we present a case of immune thrombocytopenia in the setting of acute liver failure due to coexisting diagnoses of hepatitis B virus and autoimmune hepatitis. Our patient underwent orthotopic liver transplantation and recovered hemostatic platelet counts after treatment with romiplostim, a thrombopoietin receptor agonist, 51 days after transplantation. To our knowledge, this is the first case report of immune thrombocytopenia secondary to both hepatitis B virus and autoimmune hepatitis in a patient with acute liver failure.
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http://dx.doi.org/10.1155/2021/8484106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457963PMC
September 2021

BAFF promotes heightened BCR responsiveness and manifestations of chronic GVHD after allogeneic stem cell transplantation.

Blood 2021 05;137(18):2544-2557

Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.

Patients with chronic graft-versus-host disease (cGVHD) have increased B cell-activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major histocompatibility complex-mismatched model with cGVHD-like manifestations, we first examined B-lymphopenic μMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B-cell number. Mice that later developed cGVHD had significantly increased numbers of recipient fibroblastic reticular cells with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD, because BAFF transcript in CD4+ T cells from diseased mice and patients was increased. cGVHD manifestations in mice were associated with high BAFF/B-cell ratios and persistence of B-cell receptor (BCR)-activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR responsiveness to surrogate antigen and NOTCH ligand. BAFF Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR activation or when alloantigen was present in vivo. Using T cell-depleted (BM only) BAFF Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells, and alloantibody production. We demonstrate that pathologic production of BAFF promotes an altered B-cell compartment and augments BCR responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in patients with cGVHD.
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http://dx.doi.org/10.1182/blood.2020008040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109011PMC
May 2021

Response to Central Boost Radiation Therapy in an Unresectable Retroperitoneal Sarcoma: A Case Report.

Adv Radiat Oncol 2020 Nov-Dec;5(6):1375-1379. Epub 2020 Jun 6.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

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http://dx.doi.org/10.1016/j.adro.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718497PMC
June 2020

Reduced MFAP5 expression in stroma of gallbladder adenocarcinoma and its potential diagnostic utility.

Virchows Arch 2021 Mar 7;478(3):427-434. Epub 2020 Sep 7.

Department of Pathology, Duke University Medical Center, Durham, NC, USA.

The diagnosis of invasive adenocarcinoma of the gallbladder can sometimes be challenging. The presence of true desmoplastic reaction facilitates the diagnosis of invasion. However, desmoplasia-like changes can be observed in benign gallbladder conditions, and recognition of desmoplasia may be challenging based on morphology. In this study, we tested the expression pattern of microfibril-associated protein 5 (MFAP5), a promising immunohistochemical marker for desmoplasia, in benign gallbladders with desmoplasia-like reaction and gallbladders with invasive adenocarcinoma. We also evaluated the diagnostic utility of MFAP5 in challenging cases with an interobserver agreement study. The results showed that all benign cases retained intact/positive MFAP5 staining pattern in periglandular connective tissue, whereas 79.3% (23 out of 29) of cases of adenocarcinomas demonstrated diffuse and complete loss of MFAP5 staining in the tumor stroma. Interobserver agreement was improved by 2.66 times when images of MFAP5 immunohistochemistry were provided. In conclusion, MFAP5 expression is downregulated in the desmoplastic stroma of gallbladder adenocarcinoma and may provide a useful diagnostic marker in difficult cases.
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http://dx.doi.org/10.1007/s00428-020-02925-2DOI Listing
March 2021

Epithelioid Hyalinizing Sarcoma With MGA-NUTM1 Fusion.

Am J Clin Pathol 2020 11;154(6):859-866

Department of Pathology, Duke University Medical Center, Durham, NC.

Objectives: Soft tissue sarcomas are a group of tumors derived from the mesenchymal origin. Historically, they have been classified according to morphologic and immunohistochemical characteristics. The advent of multiplexed next-generation sequencing (NGS), specifically RNA sequencing, has modified the classification of such tumors and others by determining categorization based on molecular alterations. The NUTM1 rearrangement, previously thought to be present only in carcinomas, has recently been reported in poorly differentiated high-grade sarcomas of the soft tissue. We present the first reported case of an epithelioid hyalinizing sarcoma harboring the MGA-NUTM1 fusion in an acral site.

Methods: Histopathologic, immunohistochemical, and molecular testing were performed on resection tissue.

Results: Histologically, the tumor showed an epithelioid morphology with prominent background hyalinization. Immunohistochemically, the tumor expressed CD99 and nuclear NUT-1. By NGS the tumor harbors MGA-NUTM1 fusion.

Conclusions: Our findings support more extensive use of NGS for accurate sarcoma classification and identification of potential therapeutic targets. Furthermore, they corroborate the fact that NUTM1-rearranged soft tissue tumors represent a spectrum of heterogeneous morphologic entities. This case also highlights the utility of NUT-1 immunohistochemical study as a possible screening tool for NUTM1-fused sarcomas.
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http://dx.doi.org/10.1093/ajcp/aqaa113DOI Listing
November 2020

Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle-based Chemotherapy in -deleted Mouse Models of Sarcoma.

Clin Cancer Res 2020 09 27;26(18):5036-5047. Epub 2020 Jul 27.

Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina.

Purpose: Nanoparticle-encapsulated drug formulations can improve responses to conventional chemotherapy by increasing drug retention within the tumor and by promoting a more effective antitumor immune response than free drug. New drug delivery modalities are needed in sarcomas because they are often chemoresistant cancers, but the rarity of sarcomas and the complexity of diverse subtypes makes it challenging to investigate novel drug formulations.

Experimental Design: New drug formulations can be tested in animal models of sarcomas where the therapeutic response of different formulations can be compared using mice with identical tumor-initiating mutations. Here, using Cre/loxP and CRISPR/Cas9 techniques, we generated two distinct mouse models of -deleted soft-tissue sarcoma: malignant peripheral nerve sheath tumor (MPNST) and undifferentiated pleomorphic sarcoma (UPS). We used these models to test the efficacy of chimeric polypeptide doxorubicin (CP-Dox), a nanoscale micelle formulation, in comparison with free doxorubicin.

Results: The CP-Dox formulation was superior to free doxorubicin in MPNST models. However, in UPS tumors, CP-Dox did not improve survival in comparison with free doxorubicin. While CP-Dox treatment resulted in elevated intratumoral doxorubicin concentrations in MPNSTs, this increase was absent in UPS tumors. In addition, elevation of CD8 T cells was observed exclusively in CP-Dox-treated MPNSTs, although these cells were not required for full efficacy of the CP nanoparticle-based chemotherapy.

Conclusions: These results have important implications for treating sarcomas with nanoparticle-encapsulated chemotherapy by highlighting the tumor subtype-dependent nature of therapeutic response.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641033PMC
September 2020

Medicare's Quality Payment Program Continues to Evolve: What Pathologists Need to Know to Succeed.

Authors:
Diana M Cardona

Arch Pathol Lab Med 2020 06;144(6):677-678

From the Department of Pathology, Duke University Medical Center, Durham, North Carolina.

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http://dx.doi.org/10.5858/arpa.2020-0028-EDDOI Listing
June 2020

Updates to Medicare's Quality Payment Program That May Impact You.

Arch Pathol Lab Med 2020 06;144(6):679-685

From the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Cardona); Advocacy Division, College of American Pathologists, Washington, DC (Mss Peditto and Singh); and the Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston (Dr Black-Schaffer).

Context.—: Within Medicare's Quality Payment Program, and more specifically the Merit-based Incentive Payment System, pathologists stand to potentially lose or gain approximately $2 billion during the initial 7 years of the program. If you or your group provides services to Medicare beneficiaries, you will likely need to comply with the program.

Objective.—: To avoid potential reductions in Medicare reimbursement, pathologists need to understand the requirements of these new payment programs.

Data Sources.—: Each year the Centers for Medicare & Medicaid Services publish a Final Rule detailing the program requirements and updates. 2020 marks the fourth reporting year for the Merit-based Incentive Payment System. Performance this year will impact 2022 Medicare Part B distributions by up to ±9%.

Conclusions.—: By staying up to date with the ever-evolving Merit-based Incentive Payment System requirements, pathologists will be better equipped to successfully comply with this relatively new payment system, reduce the burden of participating, understand the reporting differences of the various performance categories, and thereby be able to maximize their scoring and incentive potential.
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http://dx.doi.org/10.5858/arpa.2019-0376-RADOI Listing
June 2020

Developing Pathology Measures for the Quality Payment Program-Part I: A Quest for Meaningful Measures.

Arch Pathol Lab Med 2020 06;144(6):686-696

From the Department of Pathology, University of Colorado-Anschutz Medical Campus, Aurora (Dr Bocsi); the Department of Pathology, NorthShore University Health System, Evanston, Illinois (Dr Kang); the Advocacy Division, College of American Pathologists, Washington, DC (Mss Kennedy, Singh, and Peditto); and the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Cardona). Ms Kennedy is currently with the American Society of Clinical Oncology, Arlington, Virginia.

Context.—: Quality measures assess health care processes, outcomes, and patient perceptions associated with high-quality health care, which is commonly defined as care that is effective, safe, efficient, patient centered, equitable, and timely. Such measures are now being used in order to incentivize provision of high-quality health care.

Objective.—: To meet the goals of the Quality Payment Program, quality measures will be developed from clinical practice guidelines and relevant, peer-reviewed research identifying evidence that the measure addresses 3 areas: a high-priority aspect of health care or a specific national health goal or priority; a meaningful focus, such as leading to a desired health outcome; and a gap or variation in care.

Design.—: Within the College of American Pathologists (CAP), the Measures and Performance Assessment Subcommittee is tasked with developing useful performance measures. Participating practitioners can then select measures that are meaningful to their respective patients and practices, and reflect the quality of the services they provide.

Results.—: The CAP developed 23 quality measures for reporting to the Centers for Medicare & Medicaid Services that reflect rigorous clinical evidence and address areas in need of performance improvement.

Conclusions.—: Because the implications of reporting on these pathology-specific metrics are significant, these measures and the process by which they were designed are presented here in peer-reviewed fashion. The measures described in this article (part 1) represent recent efforts by the CAP to develop meaningful measures that reflect rigorous clinical evidence and highlight areas with opportunities for performance improvement.
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http://dx.doi.org/10.5858/arpa.2019-0377-OADOI Listing
June 2020

Developing Pathology Measures for the Quality Payment Program-Part II: Overcoming Challenges With Data Capture to Maximize Reimbursement.

Arch Pathol Lab Med 2020 06;144(6):697-705

From the Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston (Dr Kelley); the Department of Pathology, Warren Alpert Medical School of Brown University, Lifespan Academic Medical Center, Providence, Rhode Island (Dr Patil); the Advocacy Division, College of American Pathologists, Washington, DC (Mss Kennedy, Singh, and Peditto); and the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Cardona). Ms Kennedy is currently with the American Society of Clinical Oncology, Arlington, Virginia.

Context.—: Quality measures are a cornerstone in measuring physicians' performance within the Centers for Medicare & Medicaid Services' Quality Payment Program (QPP). Clinicians' performance on quality measures and other categories within the QPP determines Medicare part B payment adjustments. Driven by evidence-based clinical practice guidelines, quality measures should focus on high-priority facets of health care, support a desired patient outcome, and address an area with evidence of a gap or variation in provider performance.

Objective.—: To meet the goals of the QPP, a broad array of quality measures must be developed that allows pathologists the flexibility to choose activities and measures most meaningful to their practice and patient population while also trying to mitigate the challenges of implementation and data collection.

Design.—: In this second manuscript of the series, we present the development of additional College of American Pathologists-developed quality payment measures for use in the QPP. We also discuss the relationship of quality measure reporting with reimbursement and the challenges with capturing data for quality reporting.

Results.—: The College of American Pathologists identified 23 new measures for quality performance reporting that reflect rigorous clinical evidence and address areas in need of performance improvement.

Conclusions.—: Development of quality measures is a necessary and ongoing effort within the College of American Pathologists. Increased awareness about pathology-specific issues in measure development and reporting is essential to ensuring pathology's ability to demonstrate value and meaningfully participate in the QPP.
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http://dx.doi.org/10.5858/arpa.2019-0378-OADOI Listing
June 2020

Genome-wide CRISPR Screen to Identify Genes that Suppress Transformation in the Presence of Endogenous Kras.

Sci Rep 2019 11 20;9(1):17220. Epub 2019 Nov 20.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, 27708, USA.

Cooperating gene mutations are typically required to transform normal cells enabling growth in soft agar or in immunodeficient mice. For example, mutations in Kras and transformation-related protein 53 (Trp53) are known to transform a variety of mesenchymal and epithelial cells in vitro and in vivo. Identifying other genes that can cooperate with oncogenic Kras and substitute for Trp53 mutation has the potential to lead to new insights into mechanisms of carcinogenesis. Here, we applied a genome-wide CRISPR/Cas9 knockout screen in Kras immortalized mouse embryonic fibroblasts (MEFs) to search for genes that when mutated cooperate with oncogenic Kras to induce transformation. We also tested if mutation of the identified candidate genes could cooperate with Kras to generate primary sarcomas in mice. In addition to identifying the well-known tumor suppressor cyclin dependent kinase inhibitor 2A (Cdkn2a), whose alternative reading frame product p19 activates Trp53, we also identified other putative tumor suppressors, such as F-box/WD repeat-containing protein 7 (Fbxw7) and solute carrier family 9 member 3 (Slc9a3). Remarkably, the TCGA database indicates that both FBXW7 and SLC9A3 are commonly co-mutated with KRAS in human cancers. However, we found that only mutation of Trp53 or Cdkn2a, but not Fbxw7 or Slc9a3 can cooperate with Kras to generate primary sarcomas in mice. These results show that mutations in oncogenic Kras and either Fbxw7 or Slc9a3 are sufficient for transformation in vitro, but not for in vivo sarcomagenesis.
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http://dx.doi.org/10.1038/s41598-019-53572-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868134PMC
November 2019

Neutrophils promote tumor resistance to radiation therapy.

Proc Natl Acad Sci U S A 2019 09 28;116(37):18584-18589. Epub 2019 Aug 28.

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27708;

Nearly two-thirds of cancer patients are treated with radiation therapy (RT), often with the intent to achieve complete and permanent tumor regression (local control). RT is the primary treatment modality used to achieve local control for many malignancies, including locally advanced cervical cancer, head and neck cancer, and lung cancer. The addition of concurrent platinum-based radiosensitizing chemotherapy improves local control and patient survival. Enhanced outcomes with concurrent chemoradiotherapy may result from increased direct killing of tumor cells and effects on nontumor cell populations. Many patients treated with concurrent chemoradiotherapy exhibit a decline in neutrophil count, but the effects of neutrophils on radiation therapy are controversial. To investigate the clinical significance of neutrophils in the response to RT, we examined patient outcomes and circulating neutrophil counts in cervical cancer patients treated with definitive chemoradiation. Although pretreatment neutrophil count did not correlate with outcome, lower absolute neutrophil count after starting concurrent chemoradiotherapy was associated with higher rates of local control, metastasis-free survival, and overall survival. To define the role of neutrophils in tumor response to RT, we used genetic and pharmacological approaches to deplete neutrophils in an autochthonous mouse model of soft tissue sarcoma. Neutrophil depletion prior to image-guided focal irradiation improved tumor response to RT. Our results indicate that neutrophils promote resistance to radiation therapy. The efficacy of chemoradiotherapy may depend on the impact of treatment on peripheral neutrophil count, which has the potential to serve as an inexpensive and widely available biomarker.
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http://dx.doi.org/10.1073/pnas.1901562116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744874PMC
September 2019

The Fusion Oncogene FUS-CHOP Drives Sarcomagenesis of High-Grade Spindle Cell Sarcomas in Mice.

Sarcoma 2019 25;2019:1340261. Epub 2019 Jul 25.

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27708, USA.

Myxoid liposarcoma is a malignant soft tissue sarcoma characterized by a pathognomonic t(12;16)(q13;p11) translocation that produces a fusion oncoprotein, FUS-CHOP. This cancer is remarkably sensitive to radiotherapy and exhibits a unique pattern of extrapulmonary metastasis. Here, we report the generation and characterization of a spatially and temporally restricted mouse model of sarcoma driven by FUS-CHOP. Using different Cre drivers in the adipocyte lineage, we initiated tumorigenesis by expressing FUS-CHOP in + mesenchymal progenitor cells. In contrast, expression of FUS-CHOP in more differentiated cells does not form tumors , and early expression of the oncoprotein during embryogenesis is lethal. We also employ electroporation and CRISPR technology to rapidly generate spatially and temporally restricted mouse models of high-grade FUS-CHOP-driven sarcomas for preclinical studies.
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http://dx.doi.org/10.1155/2019/1340261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683777PMC
July 2019

LI-RADS Treatment Response Algorithm: Performance and Diagnostic Accuracy.

Radiology 2019 07 30;292(1):226-234. Epub 2019 Apr 30.

From the Department of Radiology (E.L.S., M.C., C.M.M., B.C.A., E.B., G.L.J., C.Y.K., J.R., M.R.B.), Department of Pathology (D.M.C.), Division of Gastroenterology, Department of Medicine (L.Y.K., M.R.B.), and Center for Advanced Magnetic Resonance Development (G.L.J., M.R.B.), Duke University Medical Center, Box 3808, Durham, NC; and Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY (R.K.D.).

Background In 2017, the Liver Imaging Reporting and Data System (LI-RADS) included an algorithm for the assessment of hepatocellular carcinoma (HCC) treated with local-regional therapy. The aim of the algorithm was to enable standardized evaluation of treatment response to guide subsequent therapy. However, the performance of the algorithm has not yet been validated in the literature. Purpose To evaluate the performance of the LI-RADS 2017 Treatment Response algorithm for assessing the histopathologic viability of HCC treated with bland arterial embolization. Materials and Methods This retrospective study included patients who underwent bland arterial embolization for HCC between 2006 and 2016 and subsequent liver transplantation. Three radiologists independently assessed all treated lesions by using the CT/MRI LI-RADS 2017 Treatment Response algorithm. Radiology and posttransplant histopathology reports were then compared. Lesions were categorized on the basis of explant pathologic findings as either completely (100%) or incompletely (<100%) necrotic, and performance characteristics and predictive values for the LI-RADS Treatment Response (LR-TR) Viable and Nonviable categories were calculated for each reader. Interreader association was calculated by using the Fleiss κ. Results A total of 45 adults (mean age, 57.1 years ± 8.2; 13 women) with 63 total lesions were included. For predicting incomplete histopathologic tumor necrosis, the accuracy of the LR-TR Viable category for the three readers was 60%-65%, and the positive predictive value was 86%-96%. For predicting complete histopathologic tumor necrosis, the accuracy of the LR-TR Nonviable category was 67%-71%, and the negative predictive value was 81%-87%. By consensus, 17 (27%) of 63 lesions were categorized as LR-TR Equivocal, and 12 of these lesions were incompletely necrotic. Interreader association for the LR-TR category was moderate (κ = 0.55; 95% confidence interval: 0.47, 0.67). Conclusion The Liver Imaging Reporting and Data System 2017 Treatment Response algorithm had high predictive value and moderate interreader association for the histopathologic viability of hepatocellular carcinoma treated with bland arterial embolization when lesions were assessed as Viable or Nonviable. © RSNA, 2019 See also the editorial by Gervais in this issue.
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http://dx.doi.org/10.1148/radiol.2019182135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614909PMC
July 2019

Investigating a chimeric anti-mouse PDGFRα antibody as a radiosensitizer in primary mouse sarcomas.

EBioMedicine 2019 Feb 31;40:224-230. Epub 2019 Jan 31.

Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, United States; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, United States. Electronic address:

Background: Olaratumab (LY3012207/IMC-3G3/Lartruvo™) is a fully human monoclonal antibody specific for platelet-derived growth factor receptor alpha (PDGFRα). Phase Ib/II trial results of olaratumab plus doxorubicin in adult patients with advanced soft tissue sarcoma (STS) supported accelerated FDA approval of this regimen. Radiation therapy (RT) is frequently used for high-risk localized STS. However, olaratumab has not been tested with concurrent RT. Here, we evaluate the chimeric anti-mouse PDGFRα antibody 1E10Fc as a radiosensitizer in a primary mouse model of STS.

Methods: Primary STS were initiated in mice. When tumors reached 70 mm, mice were allocated into treatment groups: 1) isotype, 2) 1E10Fc, 3) isotype + RT, 4) 1E10Fc + RT. 1E10Fc or isotype was given biweekly. RT (25 Gy delivered in 5 daily 5 Gy fractions) was initiated on Day 0 with first drug treatment. Tumors were measured 3× per week. Upon reaching 900 mm, tumors and lungs were harvested. A two-way ANOVA was performed to compare tumor growth delay. Primary tumors were stained for CD31 and PDGFRα and lungs were assessed for micrometastases. A Chi-square test was performed to compare the development of micrometastases in the lungs after treatment with 1E10Fc or isotype.

Findings: RT significantly delayed time to tumor quintupling compared to no RT (p < 0·0001) [two-way ANOVA], but no difference in tumor growth was seen between mice receiving isotype or 1E10Fc treatment regardless of concurrent RT. Lower microvessel density was observed in the 1E10Fc + RT group. Fewer mice treated with 1E10Fc had micrometastases, but this difference was not statistically significant (p < 0·09).

Interpretation: 1E10Fc did not act as a radiosensitizer in this primary STS model.

Funding: This study was funded by a research agreement from Eli Lilly and Company.
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http://dx.doi.org/10.1016/j.ebiom.2019.01.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413473PMC
February 2019

SYK inhibitor entospletinib prevents ocular and skin GVHD in mice.

JCI Insight 2018 10 4;3(19). Epub 2018 Oct 4.

Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA.

Graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HCT). The tyrosine kinase SYK contributes to both acute and chronic GVHD development, making it an attractive target for GVHD prevention. Entospletinib (ENTO) is a second-generation highly selective SYK inhibitor with a high safety profile. Potential utility of ENTO as GVHD prophylaxis in patients was examined using a preclinical mouse model of eye and skin GVHD and ENTO-compounded chow. We found that early SYK inhibition improved blood immune cell reconstitution in GVHD mice and prolonged survival, with 60% of mice surviving to day +120 compared with 10% of mice treated with placebo. Compared with mice receiving placebo, mice receiving ENTO had dramatic improvements in clinical eye scores, alopecia scores, and skin scores. Infiltrating SYK+ cells expressing B220 or F4/80, resembling SYK+ cells found in lichenoid skin lesions of chronic GVHD patients, were abundant in the skin of placebo mice but were rare in ENTO-treated mice. Thus, ENTO given early after HCT safely prevented GVHD.
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http://dx.doi.org/10.1172/jci.insight.122430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237454PMC
October 2018

Metastatic squamous cell carcinoma with pseudoangiosarcomatous features and aberrant expression of vascular markers.

Pathol Res Pract 2018 Oct 12;214(10):1732-1737. Epub 2018 Jun 12.

Duke University Medical Center, Department of Pathology, Durham, NC, United States. Electronic address:

Squamous cell carcinoma with pseudoangiosarcomatous features is a rare but well-recognized variant of squamous cell carcinoma. These tumors exhibit complex anastomosing channels lined by neoplastic cells, histologically mimicking a vasoformative mesenchymal tumor. Immunohistochemically, the published cases expressed epithelial markers and were consistently negative for vascular markers. Squamous cell carcinoma with pseudoangiosarcomatous features and aberrant expression of vascular markers has never been reported. Herein, we report two cases of metastatic poorly-differentiated squamous cell carcinoma with pseudoangiosarcomatous morphologic features which showed immunoreactivity for vascular markers (CD31, Fli-1, and ERG). One case (left thigh skin squamous cell carcinoma with abdominal wall metastasis) showed strong and diffuse positivity for vascular markers, and the final diagnosis was confirmed with electron microscopy. The second case (squamous cell carcinoma of unknown primary site with bone metastasis) showed patchy positivity for both squamous and vascular markers. This is the first report of squamous cell carcinoma with pseudoangiosarcomatous features and aberrant expression of vascular markers, which resembles angiosarcoma both morphologically and immunohistochemically, and may represent a potential diagnostic pitfall. It is of crucial importance for pathologists to be aware of metastatic squamous cell carcinoma with such unique features, so that misdiagnosis and inappropriate treatment will be avoided.
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http://dx.doi.org/10.1016/j.prp.2018.06.006DOI Listing
October 2018

Brincidofovir (CMX001) Toxicity Associated With Epithelial Apoptosis and Crypt Drop Out in a Hematopoietic Cell Transplant Patient: Challenges in Distinguishing Drug Toxicity From GVHD.

J Pediatr Hematol Oncol 2018 08;40(6):e364-e368

Departments of Pathology.

Brincidofovir (CMX001) is an oral agent with activity against double-strand DNA viruses undergoing clinical trials in immunocompromised patients. We report a patient clinically diagnosed with brincidofovir-related gastrointestinal (GI) toxicity and his histologic findings. A 2-year-old boy with medulloblastoma undergoing autologous hematopoietic cell transplantation developed adenovirus viremia 9 days posttransplant. After initial treatment with intravenous cidofovir he was started on oral brincidofovir as part of a clinical trial. He developed hematochezia, anorexia, and emesis 11 weeks later. Sigmoid colon biopsy showed marked crypt drop out, moderate epithelial apoptosis, and lamina propria edema. The pathologic diagnosis was drug-related injury versus infection. Brincidofovir toxicity was diagnosed clinically and the drug was discontinued. His GI symptoms improved in 2 weeks with supportive care and octreotide. Brincidofovir causes GI toxicity and histologically demonstrates epithelial apoptosis and crypt injury, similar to graft versus host disease and mycophenolate mofetil toxicity.
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http://dx.doi.org/10.1097/MPH.0000000000001227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059994PMC
August 2018

Genomic Status of Potentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors.

Cancer Res 2018 07 2;78(13):3672-3687. Epub 2018 May 2.

Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.

Malignant peripheral nerve sheath tumors (MPNST) are highly resistant sarcomas that occur in up to 13% of individuals with neurofibromatosis type I (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in and , with progressive amplifications of , and To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and ablation ( ; referred to as NF1-MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPNSTs with MPNSTs derived from (NF1-P53) and (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs. Longitudinal genomic analysis reveals a positive selection for MET and HGF copy number gain early in malignant peripheral nerve sheath tumor progression. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235171PMC
July 2018

Use of the National Institutes of Health Consensus Guidelines Improves the Diagnostic Sensitivity of Gastrointestinal Graft-Versus-Host Disease.

Arch Pathol Lab Med 2018 09 26;142(9):1098-1105. Epub 2018 Apr 26.

From the Departments of Pathology (Drs Cardona, Detweiler, Shealy, and Howell) and Internal Medicine (Drs Sung, Wild, Poleski, Balmadrid, and Sullivan), Duke University Medical Center, Durham, North Carolina; and the Department of Biostatistics (Ms Cirrincione), Duke Cancer Institute, Durham, North Carolina.

Context: - Graft-versus-host disease of the gastrointestinal tract is a common complication of hematopoietic stem cell transplant associated with significant morbidity and mortality. Accurate diagnosis can be difficult and is a truly clinicopathologic endeavor.

Objectives: - To assess the diagnostic sensitivity of gastrointestinal graft-versus-host disease using the 2015 National Institutes of Health (NIH) histology consensus guidelines and to analyze histologic findings that support the guidelines.

Design: - Patients with allogeneic hematopoietic stem cell transplants were identified via a retrospective search of our electronic medical records from January 1, 2005, to January 1, 2011. Endoscopies with available histology were reviewed by 2 pathologists using the 2015 NIH guidelines. The clinical diagnosis was used as the gold standard. A nontransplant set of endoscopic biopsies was used as a control.

Results: - Of the 250 total endoscopies, 217 (87%) had a clinical diagnosis of gastrointestinal graft-versus-host disease. Use of the NIH consensus guidelines showed a sensitivity of 86% and a specificity of 65%. Thirty-seven of 58 (64%) cases with an initial false-negative histopathologic diagnosis were diagnosed as graft-versus-host disease on our review.

Conclusions: - Use of the NIH histology consensus guidelines results in a high sensitivity and specificity, thereby decreasing false-negatives. Additionally, use of the NIH guidelines aids in creating uniformity and diagnostic clarity. Correlation with clinical and laboratory findings is critical in evaluating the differential diagnosis and to avoid false-positives. As expected, increased apoptosis with decreased inflammation was associated with a pathologic diagnosis of graft-versus-host disease and supports the NIH guidelines.
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http://dx.doi.org/10.5858/arpa.2017-0054-OADOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057297PMC
September 2018

Metastatic Renal Cell Carcinoma as Solitary Subcentimeter Polypoid Gastric Mucosal Lesions: Clinicopathologic Analysis of Five Cases.

Gastroenterology Res 2018 Feb 23;11(1):25-30. Epub 2018 Feb 23.

Department of Pathology, Duke University Medical Center, Durham, NC, USA.

Background: The stomach is an uncommon site for metastatic carcinoma. Approximately 6% of renal cell carcinomas (RCCs) may metastasize to the stomach. The majority of the reported metastatic RCCs in the stomach presented as large masses or ulcers greater than a centimeter in size. It is very rare to encounter metastatic RCC as a solitary small polypoid gastric mucosal lesion.

Methods: In this study, we collected surgical pathology cases of gastric metastasis from RCC that measured 1.0 cm or less at the time of endoscopy. The clinicopathological characteristics were analyzed.

Results: Five patients with subcentimeter metastatic RCC involving the gastric mucosa were identified. The clinical presentation for upper endoscopic examination was non-specific. Two of the five patients did not have a known history of RCC. In the three patients with a previous history of RCC, the interval from primary RCC diagnosis to the detection of gastric mucosal metastasis was 5, 6, and 10 years, respectively. Endoscopically, all the lesions were solitary, ranging in size from 0.4 to 1 cm. Histologically, all five cases were of the clear cell type consisting of a bland clear cell proliferation within the lamina propria. Although the tumor cells were relatively bland, the presence of clear cytoplasm, nuclear membrane irregularity, occasional enlarged hyperchromatic atypical nuclei, and destructive growth in the center of the lesion should promote immunohistochemical workup. Immunohistochemically, the RCC cells exhibited at least patchy immunoreactivity for cytokeratin and RCC markers. In two cases, there were many CD68 positive foamy histiocytes intermingled with the tumor cells.

Conclusion: Metastatic RCC can rarely present as subcentimeter polypoid gastric mucosal lesions. The remote or unknown history of RCC, the non-specific endoscopic appearance, and the bland histological features may lead to a potential diagnostic pitfall. It is of importance to raise the awareness of such an unusual presentation of metastatic RCC in the stomach and to include metastatic RCC in the differential diagnosis for gastric mucosal polyps with clear cell morphology.
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http://dx.doi.org/10.14740/gr952wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827898PMC
February 2018

Late Gastrointestinal Complications of Allogeneic Hematopoietic Stem Cell Transplantation in Adults.

Biol Blood Marrow Transplant 2018 04 12;24(4):734-740. Epub 2017 Dec 12.

Division of Hematologic Malignancies and Cellular Therapy, Duke Cancer Institute, Duke University, Durham, North Carolina.

Gastrointestinal (GI) complications including graft-versus-host disease (GVHD) are a major cause of morbidity and mortality in allogenic stem transplant recipients. Although several studies have previously looked into the acute GI complications, fewer smaller studies have reported late complications. In this large study we focus on the late (100 days post-transplant) GI complications in allogenic stem transplant recipients. In this single-center, retrospective study of all adult allogenic stem cell transplant recipients who had their transplant at Duke University over a 6-year period, 479 patients underwent allogenic stem cell transplant, of whom 392 recipients survived for at least 100 days post-transplant. Late GI symptoms were noted in 71 patients, prompting endoscopic evaluation. The primary endpoint of our study was the diagnosis of GI-GVHD based on endoscopic findings, whereas overall survival and nonrelapse mortality were the secondary endpoints. Of the 71 patients who underwent endoscopy, 45 (63%) had GI-GVHD. Of these 45 patients, 39 (87%) had late acute GVHD, 1 (2%) had chronic GVHD, and 5 patients (11%) had overlap disease. Of the patients who did not have GVHD, the symptoms were mostly related to infectious and inflammatory causes. Less common causes included drug toxicity, food intolerance, disease relapse, and motility issues. In a multivariate analysis the factors most indicative of GI-GVHD were histologic findings of apoptosis on the tissue specimen (odds ratio, 2.35; 95% confidence interval, 1.18 to 4.70; P = .015) and clinical findings of diarrhea (odds ratio, 5.43; 95% confidence interval, 1.25 to 23.54; P = .024). The median survival time from the first endoscopy was 8.5 months. The incidence of nonrelapse mortality at 6 months was 31% in patients with GI-GVHD and 19% in patients without GI-GVHD (P = .42). All patients with GI-GVHD were on steroid therapy, and 31% of them received total parenteral nutrition. In our population close to one-fifth of allogenic transplant recipients experienced late GI complications, warranting endoscopic evaluation. Most of these patients were found to have GI-GVHD that had a high incidence of nonrelapse mortality at 6 months and close to one-third of these patients needed total parenteral nutrition.
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http://dx.doi.org/10.1016/j.bbmt.2017.12.772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415754PMC
April 2018

Porcine Esophageal Submucosal Gland Culture Model Shows Capacity for Proliferation and Differentiation.

Cell Mol Gastroenterol Hepatol 2017 Nov 4;4(3):385-404. Epub 2017 Aug 4.

Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina.

Background & Aims: Although cells comprising esophageal submucosal glands (ESMGs) represent a potential progenitor cell niche, new models are needed to understand their capacity to proliferate and differentiate. By histologic appearance, ESMGs have been associated with both overlying normal squamous epithelium and columnar epithelium. Our aim was to assess ESMG proliferation and differentiation in a 3-dimensional culture model.

Methods: We evaluated proliferation in human ESMGs from normal and diseased tissue by proliferating cell nuclear antigen immunohistochemistry. Next, we compared 5-ethynyl-2'-deoxyuridine labeling in porcine ESMGs in vivo before and after esophageal injury with a novel in vitro porcine organoid ESMG model. Microarray analysis of ESMGs in culture was compared with squamous epithelium and fresh ESMGs.

Results: Marked proliferation was observed in human ESMGs of diseased tissue. This activated ESMG state was recapitulated after esophageal injury in an in vivo porcine model, ESMGs assumed a ductal appearance with increased proliferation compared with control. Isolated and cultured porcine ESMGs produced buds with actively cycling cells and passaged to form epidermal growth factor-dependent spheroids. These spheroids were highly proliferative and were passaged multiple times. Two phenotypes of spheroids were identified: solid squamous (P63+) and hollow/ductal (cytokeratin 7+). Microarray analysis showed spheroids to be distinct from parent ESMGs and enriched for columnar transcripts.

Conclusions: Our results suggest that the activated ESMG state, seen in both human disease and our porcine model, may provide a source of cells to repopulate damaged epithelium in a normal manner (squamous) or abnormally (columnar epithelium). This culture model will allow the evaluation of factors that drive ESMGs in the regeneration of injured epithelium. The raw microarray data have been uploaded to the National Center for Biotechnology Information Gene Expression Omnibus (accession number: GSE100543).
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http://dx.doi.org/10.1016/j.jcmgh.2017.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602779PMC
November 2017

Generation and comparison of CRISPR-Cas9 and Cre-mediated genetically engineered mouse models of sarcoma.

Nat Commun 2017 07 10;8:15999. Epub 2017 Jul 10.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Genetically engineered mouse models that employ site-specific recombinase technology are important tools for cancer research but can be costly and time-consuming. The CRISPR-Cas9 system has been adapted to generate autochthonous tumours in mice, but how these tumours compare to tumours generated by conventional recombinase technology remains to be fully explored. Here we use CRISPR-Cas9 to generate multiple subtypes of primary sarcomas efficiently in wild type and genetically engineered mice. These data demonstrate that CRISPR-Cas9 can be used to generate multiple subtypes of soft tissue sarcomas in mice. Primary sarcomas generated with CRISPR-Cas9 and Cre recombinase technology had similar histology, growth kinetics, copy number variation and mutational load as assessed by whole exome sequencing. These results show that sarcomas generated with CRISPR-Cas9 technology are similar to sarcomas generated with conventional modelling techniques and suggest that CRISPR-Cas9 can be used to more rapidly generate genotypically and phenotypically similar cancers.
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http://dx.doi.org/10.1038/ncomms15999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508130PMC
July 2017

NF1 Hematopoietic Cells Accelerate Malignant Peripheral Nerve Sheath Tumor Development without Altering Chemotherapy Response.

Cancer Res 2017 08 23;77(16):4486-4497. Epub 2017 Jun 23.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Haploinsufficiency in the tumor suppressor NF1 contributes to the pathobiology of neurofibromatosis type 1, but a related role has not been established in malignant peripheral nerve sheath tumors (MPNST) where NF1 mutations also occur. Patients with NF1-associated MPNST appear to have worse outcomes than patients with sporadic MPNST, but the mechanism underlying this correlation is not understood. To define the impact of stromal genetics on the biology of this malignancy, we developed unique mouse models that reflect the genetics of patient-associated MPNST. Specifically, we used adenovirus-Cre injections to generate MPNST in Nf1; Ink4a/Arf and Nf1; Ink4a/Arf paired littermate mice to model tumors from NF1-wild-type and NF1-associated patients, respectively. In these models, Nf1 haploinsufficiency in hematopoietic cells accelerated tumor onset and increased levels of tumor-infiltrating immune cells comprised of CD11b cells, monocytes, and mast cells. We observed that mast cells were also enriched in human NF1-associated MPNST. In a coclinical trial to examine how the tumor microenvironment influences the response to multiagent chemotherapy, we found that stromal Nf1 status had no effect. Taken together, our results clarify the role of the NF1-haploinsufficient tumor microenvironment in MPNST. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839126PMC
August 2017

Current Valuation of Pathology Service.

Adv Anat Pathol 2017 Jul;24(4):222-225

*Department of Pathology, Robert J Tomsich Institute of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH †Department of Pathology, Duke University Medical Center, Durham, NC ‡College of American Pathologists, Washington, DC §Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Health care reform has accelerated as the existing health care system undergoes continuing financial stress. Medicare's new value-based payment system, commonly referred to as MACRA, provides opportunities for physicians to participate in this new system in a variety of ways. However, many of the value-based adjustments are based on existing valuations of services through traditional mechanisms. To achieve appropriate valuation of pathologist's services in the new payment models, it is imperative that we continue to achieve proper valuation of services through the traditional mechanisms.
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http://dx.doi.org/10.1097/PAP.0000000000000156DOI Listing
July 2017

Identification of mutation: clinical use of microarray.

Clin Case Rep 2017 06 10;5(6):980-985. Epub 2017 May 10.

Division of Medical Genetics Department of Pediatrics Duke University Health System Durham North Carolina.

We report a case of an infant with congenital tufting enteropathy (CTE) who presented with severe failure to thrive despite multiple interventions. This study illustrates that CTE may be missed by endoscopy, and the use of chromosomal microarray and immunohistological analysis may be integral to diagnosis.
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http://dx.doi.org/10.1002/ccr3.914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457984PMC
June 2017
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