Publications by authors named "Benjamin J Gigliotti"

5 Publications

  • Page 1 of 1

Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma.

Cancer Cell 2018 08;34(2):242-255.e5

Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Thyroid Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Hürthle cell carcinoma of the thyroid (HCC) is a form of thyroid cancer recalcitrant to radioiodine therapy that exhibits an accumulation of mitochondria. We performed whole-exome sequencing on a cohort of primary, recurrent, and metastatic tumors, and identified recurrent mutations in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter. Parallel analysis of mtDNA revealed recurrent homoplasmic mutations in subunits of complex I of the electron transport chain. Analysis of DNA copy-number alterations uncovered widespread loss of chromosomes culminating in near-haploid chromosomal content in a large fraction of HCC, which was maintained during metastatic spread. This work uncovers a distinct molecular origin of HCC compared with other thyroid malignancies.
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http://dx.doi.org/10.1016/j.ccell.2018.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121811PMC
August 2018

Circulating BRAF Levels Correlate with Treatment in Patients with Thyroid Carcinoma.

Thyroid 2018 03 27;28(3):328-339. Epub 2018 Feb 27.

1 Department of Surgery, Massachusetts General Hospital , Boston, Massachusetts.

Background: BRAF is the most common mutation in papillary thyroid carcinoma (PTC) and can be associated with aggressive disease. Previously, a highly sensitive blood RNA-based BRAF assay was reported. The objective of this study was to assess the correlation of BRAF circulating tumor RNA levels with surgical and medical treatment.

Methods: Circulating BRAF levels were assessed in (i) a murine model of undifferentiated (anaplastic) thyroid carcinoma with known BRAF mutation undergoing BRAF-inhibitor (BRAFi) treatment, and (ii) in 111 patients enrolled prior to thyroidectomy (n = 86) or treatment of advanced recurrent or metastatic PTC (n = 25). Blood samples were drawn for BRAF analysis before and after treatment. Testing characteristics were assessed and positivity criteria optimized. Changes in blood BRAF values were assessed and compared to clinical characteristics and response to therapy.

Results: In a murine model of anaplastic thyroid carcinoma with BRAF mutation, blood BRAF RNA correlated with tumor volume in animals treated with BRAFi. In tissue BRAF-positive (n = 36) patients undergoing initial surgery for PTC, blood BRAF levels declined postoperatively (median 370.0-178.5 fg/ng; p = 0.002). In four patients with metastatic or poorly differentiated thyroid carcinoma receiving targeted therapies, blood BRAF declined following therapy and corresponded with radiographic evidence of partial response or stable disease.

Conclusions: This study shows the correlation of blood BRAF levels in response to treatment in both an established animal model of thyroid cancer and in patients with BRAF-positive tumors with all stages of disease. This assay represents an alternative biomarker in patients with positive thyroglobulin antibodies, and tumors, which do not express thyroglobulin.
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http://dx.doi.org/10.1089/thy.2017.0322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865613PMC
March 2018

PD-L1 and IDO1 Are Expressed in Poorly Differentiated Thyroid Carcinoma.

Endocr Pathol 2018 Mar;29(1):59-67

Department of Pathology, Massachusetts General Hospital, Warren 219, 55 Fruit Street, Boston, MA, 02114, USA.

Poorly differentiated thyroid carcinoma (PDTC) is an aggressive form of thyroid cancer that currently has limited effective treatment options. Immune checkpoint inhibitors (ICIs) have shown to be an effective treatment for a variety of carcinomas. In this study, we explore whether immune checkpoint pathways, such as programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1), are activated in a cohort of patients with PDTC to determine whether ICIs may be an effective therapy for these patients. PDTC from 28 patients were stained for IDO1, PD-L1, and CD8 using immunohistochemistry. Staining was scored using an H-score, and PD-L1 and IDO1 expression was correlated with clinicopathologic characteristics. Positivity for PD-L1 and IDO1 was set at an H-score cutoff of five. Twenty-five percent (n = 7/28) of the PDTC were positive for PD-L1 expression. Twenty-nine percent (n = 2/7) of the PD-L1 positive PDTCs also co-expressed IDO1. The expression of PD-L1 in PDTC was significantly associated with tumor size and multifocality, with a non-significant trend towards associations with older age, extrathyroidal extension, presence of metastasis, higher stage, increased number of CD8+ T cells, and decreased disease-free and overall survival. PD-L1 expression occurs in a subset of PDTC, and is associated with a subset of clinical features of aggressive thyroid disease. Given the limited effective treatments for this patient population, consideration for ICIs as monotherapy or in combination with an IDO1 inhibitor should be explored as a novel treatment modality for patients with PDTC.
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http://dx.doi.org/10.1007/s12022-018-9514-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500591PMC
March 2018

In vivo prostaglandin E2 treatment alters the bone marrow microenvironment and preferentially expands short-term hematopoietic stem cells.

Blood 2009 Nov 2;114(19):4054-63. Epub 2009 Sep 2.

Endocrine Division, University of Rochester School of Medicine, Rochester, NY 14642, USA.

Microenvironmental signals can determine hematopoietic stem cell (HSC) fate choices both directly and through stimulation of niche cells. In the bone marrow, prostaglandin E(2) (PGE(2)) is known to affect both osteoblasts and osteoclasts, whereas in vitro it expands HSCs and affects differentiation of hematopoietic progenitors. We hypothesized that in vivo PGE(2) treatment could expand HSCs through effects on both HSCs and their microenvironment. PGE(2)-treated mice had significantly decreased number of bone trabeculae, suggesting disruption of their microarchitecture. In addition, in vivo PGE(2) increased lineage(-) Sca-1(+) c-kit(+) bone marrow cells without inhibiting their differentiation. However, detailed immunophenotyping demonstrated a PGE(2)-dependent increase in short-term HSCs/multipotent progenitors (ST-HSCs/MPPs) only. Bone marrow cells transplanted from PGE(2) versus vehicle-treated donors had superior lymphomyeloid reconstitution, which ceased by 16 weeks, also suggesting that ST-HSCs were preferentially expanded. This was confirmed by serial transplantation studies. Thus in vivo PGE(2) treatment, probably through a combination of direct and microenvironmental actions, preferentially expands ST-HSCs in the absence of marrow injury, with no negative impact on hematopoietic progenitors or long-term HSCs. These novel effects of PGE(2) could be exploited clinically to increase donor ST-HSCs, which are highly proliferative and could accelerate hematopoietic recovery after stem cell transplantation.
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http://dx.doi.org/10.1182/blood-2009-03-205823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774547PMC
November 2009

Parathyroid hormone stimulates expression of the Notch ligand Jagged1 in osteoblastic cells.

Bone 2006 Sep 2;39(3):485-93. Epub 2006 May 2.

Endocrine Division, Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Avenue Box 693 Rochester, NY 14642, USA.

We previously demonstrated that activation of the Parathyroid Hormone Receptor (PTH1R) in osteoblastic cells increases the Notch ligand Jagged1 and expands hematopoietic stem cells (HSC) through Notch signaling. However, regulation of Jagged1 by PTH in osteoblasts is poorly understood. The present study demonstrates that PTH treatment increases Jagged1 levels in a subpopulation of osteoblastic cells in vivo and in UMR106 osteoblastic cells in vitro. Since PTH(1-34) activates both Adenylate Cyclase/Protein Kinase A (AC/PKA) and Protein Kinase C (PKC) downstream of the PTH1R in osteoblastic cells, we independently determined the effect of either pathway on Jagged1. Activation of AC with Forskolin or PKA with PTH(1-31) or cell-permeable cAMP analogues increased osteoblastic Jagged1. This PTH-dependent Jagged1 increase was blocked by H89 and PKI, specific PKA inhibitors. In contrast, PKC activation with phorbol ester (PMA) or PTH(13-34) did not stimulate Jagged1 expression, and PTH-dependent Jagged1 stimulation was not blocked by Gö6976, a conventional PKC inhibitor. Therefore, PTH treatment stimulates osteoblastic Jagged1 mainly through the AC/PKA signaling pathway downstream of the PTH1R. Since Jagged1/Notch signaling has been implicated not only in stromal-HSC interactions but also in osteoblastic differentiation, Jagged1 may play a critical role in mediating the PTH-dependent expansion of HSC, as well as the anabolic effect of PTH in bone.
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http://dx.doi.org/10.1016/j.bone.2006.03.002DOI Listing
September 2006