Publications by authors named "Martha M Quezado"

48 Publications

Gastrointestinal Computed Tomography Findings in Chronic Granulomatous Disease with Subgroup Clinicopathologic Analysis.

Dig Dis Sci 2021 May 1. Epub 2021 May 1.

Abdominal Imaging, Division of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency which can lead to gastrointestinal (GI) complications including inflammatory bowel disease. Radiographic findings in this cohort have not been well described.

Aims: To describe the frequency and spectrum of gastrointestinal abnormalities seen on computed tomography (CT) in patients with CGD and determine whether radiography was predictive of endoscopic or histopathologic inflammatory findings.

Methods: A retrospective review was conducted on 141 consecutive CGD patients seen at the National Institutes of Health between 1988 and 2011. All corresponding CTs were reviewed for gastrointestinal abnormalities including wall thickening. Endoscopic and histopathologic findings were reviewed in subjects with documented endoscopy within 30 days of an imaging study. Findings were compared between patients with and without wall thickening on CT to determine whether bowel wall thickening was predictive of endoscopic or histologic inflammatory findings.

Results: Two hundred and ninety-two CTs were reviewed. GI wall thickening was present on CT in 61% of patients (n = 86). Among a subgroup of 20 patients who underwent endoscopy at the time of their imaging, there was a statistically significant correlation between radiographic gastrointestinal wall thickening and endoscopic inflammation in the same intestinal segment (p = 0.035). Additionally, there was a significant correlation between radiographic gastrointestinal wall thickening and inflammatory features on histopathology (p = 0.02).

Conclusions: GI abnormalities are commonly observed on CT in CGD patients. Bowel wall thickening correlates with endoscopic and histopathologic evidence of inflammation. These findings may be used to better facilitate directed endoscopic assessment and histopathologic sampling in patients with CGD.
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http://dx.doi.org/10.1007/s10620-021-06978-4DOI Listing
May 2021

A case of Carney triad complicated by renal cell carcinoma and a germline SDHA pathogenic variant.

Endocrinol Diabetes Metab Case Rep 2021 Mar 28;2021. Epub 2021 Mar 28.

Section on Endocrinology and Genetics, National Institutes of Health, Bethesda, Maryland, USA.

Summary: Succinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma (PGL)/ pheochromocytoma (PHEO) syndromes, Carney dyad, and Carney triad. Carney triad is a rare multitumoral syndrome characterized by co-existing PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma (CHO). We report a case of a 57-year-old male who presented with para-aortic and gastroesophogeal masses, and a right renal superior pole lesion, which were classified as multiple PGLs, a GIST, and a clear cell renal carcinoma, respectively, on pathology following surgical resection. Additionally, a CHO was diagnosed radiologically, although no biopsy was performed. A diagnosis of Carney triad was made. SDHB immunohistochemical staining was negative for the PGL and the GIST, indicating SDH-deficiency. Interestingly, the renal cell carcinoma (RCC) stained positive for both SDHB and SDHA. Subsequent genetic screening of SDH subunit genes revealed a germline inactivating heterozygous SDHA pathogenic variant (c.91 C>T, p.R31X). Loss of heterozygosity was not detected at the tumor level for the RCC, which likely indicated the SDHA variant would not be causative of the RCC, but could still predispose to the development of neoplasias. To the knowledge of the authors this is the first reported case of an SDHA pathogenic variant in a patient with Carney triad complicated by RCC.

Learning Points: The succinate dehydrogenase enzyme is encoded by four subunit genes (SDHA, SDHB, SDHC, and SDHD; collectively referred to as SDHx), which have been implicated in several neoplasias and are classified as tumor suppressor genes. Carney triad is a rare multiple-neoplasia syndrome presenting as an association of PGLs, GISTs, and CHOs. Carney triad is most commonly associated with hypermethylation of SDHC as demonstrated in tumor tissue, but approximately 10% of cases are due to pathogenic SDHx variants. Although SDHB pathogenic variants are most commonly reported in SDH-deficient renal cell carcinoma, SDHA disease-causing variants have been reported in rare cases.
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http://dx.doi.org/10.1530/EDM-20-0170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052566PMC
March 2021

Variable expression of CXCR4 in molecular subtypes of infiltrating gliomas.

Clin Neuropathol 2021 Mar-Apr;40(2):98-107

Aim: Glioblastomas (GBMs) and diffuse intrinsic pontine gliomas (DIPGs) are infiltrating gliomas with poor prognosis. CXCR4 has been linked to glioma cell invasion, survival, proliferation, and angiogenesis. This study aimed to evaluate the expression of CXCR4 in molecular subtypes of adult and pediatric infiltrating gliomas.

Materials And Methods: We evaluated the expression of CXCR4 in 21 DIPGs and 44 adult infiltrating gliomas (25 GBM, 8 astrocytomas, and 11 oligodendrogliomas) by immunohistochemistry. Mutations in 315 cancer genes and rearrangements in 28 genes were evaluated by next-generation sequencing.

Results: CXCR4 was expressed in -DIPGs and adult infiltrating gliomas in tumor cells (28.6% and 5.6%, respectively) and endothelial cells (14.3% and 19.4%?, respectively). In adult gliomas, there was a correlation between CXCR4 expression and mutations in promoter, and loss. In contrast, CXCR4 expression was not detected in mutant gliomas. These associations were confirmed using The Cancer Genome Atlas (TCGA) database.

Conclusion: CXCR4 is expressed in a subset of DIPGs and GBMs, but it is not expressed in astrocytomas or oligodendrogliomas. CXCR4 expression is variable and it is influenced by tumor genomic alterations. It is important to consider CXCR4 expression in clinical trials that evaluate the efficacy of CXCR4 inhibitors in the treatment of gliomas.
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http://dx.doi.org/10.5414/NP301287DOI Listing
February 2021

Sickle cell disease mice have cerebral oxidative stress and vascular and white matter abnormalities.

Blood Cells Mol Dis 2021 Feb 4;86:102493. Epub 2020 Sep 4.

Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, United States of America. Electronic address:

Strokes are feared complications of sickle cell disease (SCD) and yield significant neurologic and neurocognitive deficits. However, even without detectable strokes, SCD patients have significant neurocognitive deficits in domains of learning and memory, processing speed and executive function. In these cases, mechanisms unrelated to major cerebrovascular abnormalities likely underlie these deficits. While oxidative stress and stress-related signaling pathways play a role in SCD pathophysiology, their role in cerebral injury remains unknown. We have shown that Townes and BERK SCD mice, while not having strokes, recapitulate neurocognitive deficits reported in humans. We hypothesized that cognitive deficits in SCD mice are associated with cerebral oxidative stress. We showed that SCD mice have increased levels of reactive oxygen species, protein carbonylation, and lipid peroxidation in hippocampus and cortex, thus suggesting increased cerebral oxidative stress. Further, cerebral oxidative stress was associated with caspase-3 activity alterations and vascular endothelial abnormalities, white matter changes, and disruption of the blood brain barrier, similar to those reported after ischemic/oxidative injury. Additionally, after repeated hypoxia/reoxygenation exposure, homozygous Townes had enhanced microglia activation. Our findings indicate that oxidative stress and stress-induced tissue damage is increased in susceptible brain regions, which may, in turn, contribute to neurocognitive deficits in SCD mice.
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http://dx.doi.org/10.1016/j.bcmd.2020.102493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686096PMC
February 2021

Adenoid cystic carcinoma of the salivary gland metastasizing to the pericardium and diaphragm: Report of a rare case.

Diagn Cytopathol 2021 Jan 8;49(1):E31-E35. Epub 2020 Aug 8.

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Adenoid cystic carcinoma (AdCC) is an uncommon malignancy of the salivary gland characterized by slow growth, increased risk of recurrence and poor prognosis. The annual incidence in the United States is approximately 1200 cases per year and rarely involves the body cavities.

Case Presentation: We present a case of a 48-year-old male diagnosed with AdCC of the left submandibular gland. He received his last chemotherapy in 2006 and presented with pleural metastasis. After undergoing pleurectomy and decortication procedure, pericardial fluid and biopsies from the chest wall, sixth rib, diaphragm, pleural cavity and pericardium were sent for pathologic evaluation. A diagnosis of metastatic adenoid cystic carcinoma was confirmed, including in the pericardium, pericardial fluid and diaphragm.

Conclusion: AdCC of the submandibular gland is a malignant tumor with a high mortality rate. It is very rare for AdCC to metastasize to the pericardium and diaphragm. Metastasis to uncommon sites such as seen in our case with metastases to the pericardium and diaphragm shows the aggressive and unpredictable nature of this tumor, requiring close follow up, and indicating the need for molecular profile analysis and biomarker-stratified clinical trials.
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http://dx.doi.org/10.1002/dc.24566DOI Listing
January 2021

Clinical findings in families with chordoma with and without T gene duplications and in patients with sporadic chordoma reported to the Surveillance, Epidemiology, and End Results program.

J Neurosurg 2020 Jun 19:1-10. Epub 2020 Jun 19.

1Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda.

Objective: To gain insight into the role of germline genetics in the development of chordoma, the authors evaluated data from 2 sets of patients with familial chordoma, those with and without a germline duplication of the T gene (T-dup+ vs T-dup-), which was previously identified as a susceptibility mechanism in some families. The authors then compared the patients with familial tumors to patients with sporadic chordoma in the US general population reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program through 2015.

Methods: Evaluation of family members included review of personal and family medical history, physical and neurological examination, and pre- and postcontrast MRI of the skull base and spine. Sixteen patients from 6 white families with chordoma had a chordoma diagnosis at family referral. Screening MR images of 35 relatives revealed clival lesions in 6, 4 of which were excised and confirmed to be chordoma. Thus, data were available for 20 patients with histologically confirmed familial chordoma. There were 1759 patients with histologically confirmed chordoma in SEER whose race was known.

Results: The median age at chordoma diagnosis differed across the groups: it was lowest in T-dup+ familial patients (26.8 years, range 5.3-68.4 years); intermediate in T-dup- patients (46.2 years, range 11.8-60.1 years); and highest in SEER patients (57 years, range 0-98 years). There was a marked preponderance of skull base tumors in patients with familial chordoma (93% in T-dup+ and 83% in T-dup-) versus 38% in the SEER program (37% in white, 53% in black, and 48.5% in Asian/Pacific Islander/American Indian/Alaska Native patients). Furthermore, 29% of white and 16%-17% of nonwhite SEER patients had mobile-spine chordoma, versus no patients in the familial group. Several T-dup+ familial chordoma patients had putative second/multiple primary chordomas.

Conclusions: The occurrence of young age at diagnosis, skull base presentation, or multiple primary chordomas should encourage careful review of family history for patients diagnosed with chordoma as well as screening of at-risk family members by MRI for early detection of chordoma. Furthermore, given genetic predisposition in some patients with familial chordoma, identification of a specific mutation in a family will permit surveillance to be limited to mutation carriers-and consideration should be given for imaging the entire neuraxis in any chordoma patient presenting at an early age or with a blood relative with chordoma. Finally, future studies should explore racial differences in age at diagnosis and presenting site in chordoma.
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http://dx.doi.org/10.3171/2020.4.JNS193505DOI Listing
June 2020

Locomotor mal-performance and gait adaptability deficits in sickle cell mice are associated with vascular and white matter abnormalities and oxidative stress in cerebellum.

Brain Res 2020 11 10;1746:146968. Epub 2020 Jun 10.

Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Patients with sickle cell disease (SCD) can develop strokes and as a result, present neurologic and neurocognitive deficits. However, recent studies show that even without detectable cerebral parenchymal abnormalities on imaging studies, SCD patients can have significant cognitive and motor dysfunction, which can present as early as during infancy. As the cerebellum plays a pivotal role in motor and non-motor functions including sensorimotor processing and learning, we examined cerebellar behavior in humanized SCD mice using the Erasmus ladder. Homozygous (sickling) mice had significant locomotor malperformance characterized by miscoordination and impaired locomotor gait/stepping pattern adaptability. Conversely, Townes homozygous mice had no overall deficits in motor learning, as they were able to associate a conditioning stimulus (high-pitch warning tone) with the presentation of an obstacle and learned to decrease steptimes thereby increasing speed to avoid it. While these animals had no cerebellar strokes, these locomotor and adaptive gait/stepping patterns deficits were associated with oxidative stress, as well as cerebellar vascular endothelial and white matter abnormalities and blood brain barrier disruption, suggestive of ischemic injury. Taken together, these observations suggest that motor and adaptive locomotor deficits in SCD mice mirror some of those described in SCD patients and that ischemic changes in white matter and vascular endothelium and oxidative stress are biologic correlates of those deficits. These findings point to the cerebellum as an area of the central nervous system that is vulnerable to vascular and white matter injury and support the use of SCD mice for studies of the underlying mechanisms of cerebellar dysfunction in SCD.
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http://dx.doi.org/10.1016/j.brainres.2020.146968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483603PMC
November 2020

Inhibin A as a tumor marker for primary bilateral macronodular adrenal hyperplasia.

Endocrinol Diabetes Metab Case Rep 2020 Apr 29;2020. Epub 2020 Apr 29.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Summary: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing syndrome (CS). This condition is characterized by glucocorticoid and/or mineralocorticoid excess, and is commonly regulated by aberrant G-protein coupled receptor expression may be subclinical, allowing the disease to progress for years undetected. Inhibin A is a glycoprotein hormone and tumor marker produced by certain endocrine glands including the adrenal cortex, which has not been previously investigated as a potential tumor marker for PBMAH. In the present report, serum inhibin A levels were evaluated in three patients with PBMAH before and after adrenalectomy. In all cases, serum inhibin A was elevated preoperatively and subsequently fell within the normal range after adrenalectomy. Additionally, adrenal tissues stained positive for inhibin A. We conclude that serum inhibin A levels may be a potential tumor marker for PBMAH.

Learning Points: PBMAH is a rare cause of CS. PBMAH may have an insidious presentation, allowing the disease to progress for years prior to diagnosis. Inhibin A is a heterodimeric glycoprotein hormone expressed in the gonads and adrenal cortex. Inhibin A serum concentrations are elevated in some patients with PBMAH, suggesting the potential use of this hormone as a tumor marker. Further exploration of serum inhibin A concentration, as it relates to PBMAH disease progression, is warranted to determine if this hormone could serve as an early detection marker and/or predictor of successful surgical treatment.
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http://dx.doi.org/10.1530/EDM-20-0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219132PMC
April 2020

Mobile Myxopapillary Ependymoma with Associated Filum Terminale Cyst.

World Neurosurg 2020 07 25;139:337-342. Epub 2020 Apr 25.

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Background: Intradural ependymal cysts are benign, fluid-filled cysts usually situated along the ventral surface of the spinal cord. There are previous reports of 19 intradural cysts in the literature, including one cyst of the filum terminale. Here, we report for the first time the presence of a radiographically occult filum terminale cyst associated with a myxopapillary ependymoma. We propose that mobility of the tumor may provide indirect evidence of the presence of a cyst.

Case Description: A 65-year-old male patient presented with a homogenously enhancing ovoid mass measuring 25 mm × 10 mm within the thecal sac at the L3 through L4 levels. Repeat magnetic resonance imaging demonstrated migration of the tumor 12 mm rostrally. Following the L2 through L4 laminectomy and resection of the intradural tumor, we identified a filum terminale ependymal cyst superior to the tumor, which was also resected.

Conclusions: Ependymal cysts associated with spinal tumors are rare and may be radiographically occult. The change in cyst size may explain tumor mobility. Complete resection of the cyst and histopathologic analysis is recommended to differentiate between ependymal cyst and cystic tumor tissue.
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http://dx.doi.org/10.1016/j.wneu.2020.04.095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453488PMC
July 2020

Resection of Myxopapillary Ependymoma of the Filum Terminale: 2-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2020 Feb;18(2):E40

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

We present the case of a 48-yr-old female who presented with persistent thigh pain and was found to have a heterogeneous mass caudal to the conus most consistent with a myxopapillary ependymoma. We performed L2-3 laminectomies for tumor resection. For this procedure, we used intraoperative ultrasound as well as neuromonitoring. This video illustrates the gross pathology of a myxopapillary ependymoma, effective circumferential blunt and sharp dissection of the cauda equina from the tumor, and identification, preparation, and sectioning of the filum terminale. This case also underlines the challenges of removing a large myxopapillary ependymoma when motor nerve rootlets are encapsulated in the tumor. In this case, we were obligated to enter the tumor capsule ventrally in order to dissect away cauda equina nerves passing through the tumor. The patient consented to be part of our research study.
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http://dx.doi.org/10.1093/ons/opz099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594178PMC
February 2020

CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors.

Clin Cancer Res 2019 04 17;25(8):2560-2574. Epub 2019 Jan 17.

Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California.

Purpose: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system.

Experimental Design: We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models.

Results: B7-H3 CAR T cells mediate significant antitumor activity , causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3.

Conclusions: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0432DOI Listing
April 2019

Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors.

Cancer 2019 04 8;125(8):1247-1257. Epub 2019 Jan 8.

Department of Surgery, Stanford University, Stanford, California.

Background: Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs.

Methods: Thirty-three tissue samples were analyzed: they included samples from sporadic (n = 9), von Hippel-Lindau (VHL)-related (n = 10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n = 10) as well as normal islet cells (n = 4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools.

Results: In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs.

Conclusions: MEN1 NFPanNETs have a higher rate of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs.
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http://dx.doi.org/10.1002/cncr.31930DOI Listing
April 2019

18F-FDOPA PET/CT Imaging of MAX-Related Pheochromocytoma.

J Clin Endocrinol Metab 2018 04;103(4):1574-1582

Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland.

Context: MYC-associated factor X (MAX) has been recently described as a new susceptibility pheochromocytoma (PHEO) gene with a total of ~40 reported cases. At present, no study has specifically described the functional imaging phenotype of MAX-related PHEO.

Objective, Patients, And Design: The objective of the present study was to present our experience with contrast-enhanced computed tomography (CT) and 18F-fluorodihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET)/CT in six consecutive patients (four at the initial diagnosis and two at the follow-up evaluation) with rare, but clinically important, MAX-related PHEOs. In five patients, 18F-FDOPA was also compared with other radiopharmaceutical agents.

Results: The patients had five different mutations in the MAX gene that caused disruption of Max/Myc interaction and/or abolished interaction with DNA based on in silico analyses. All but one patient developed bilateral PHEOs during their lifetime. In all cases, 18F-FDOPA PET/CT accurately visualized PHEOs that were often multiple within the same gland or bilaterally and detected more adrenal and extra-adrenal lesions than did CT (per-lesion sensitivity, 90.9% vs 52.4% for CT/magnetic resonance imaging). The two PHEOs missed on 18F-FDOPA PET/CT were <1 cm, corresponding to nodular adrenomedullary hyperplasia. 68Ga-DOTA,Tyr3-octreotate PET/CT detected fewer lesions than did 18F-FDOPA PET/CT in one of three patients, and 18F-fluorodeoxyglucose PET/CT was only faintly positive in two of four patients with underestimation of extra-adrenal lesions in one patient.

Conclusions: MAX-related PHEOs exhibit a marked 18F-FDOPA uptake, a finding that illustrates the common well-differentiated chromaffin pattern of PHEOs associated with activation of kinase signaling pathways. 18F-FDOPA PET/CT should be considered as the first-line functional imaging modality for diagnostic or follow-up evaluations for these patients.
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http://dx.doi.org/10.1210/jc.2017-02324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276705PMC
April 2018

Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors.

Ann Rheum Dis 2018 04 22;77(4):612-619. Epub 2018 Jan 22.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.

Objectives: To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in , a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype.

Methods: We studied nine patients with biallelic mutations in and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).

Results: We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth.

Conclusions: Mutations of lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.
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http://dx.doi.org/10.1136/annrheumdis-2017-212401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890629PMC
April 2018

Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview.

Hum Pathol 2017 09 24;67:1-10. Epub 2017 May 24.

Department of Pathology, Division of Neuropathology, University of California, San Francisco, CA 94143, USA.

Patients with neurofibromatosis 1 (NF1) develop multiple neurofibromas, with 8% to 15% of patients experiencing malignant peripheral nerve sheath tumor (MPNST) during their lifetime. Prediction of transformation, typically from plexiform neurofibroma, is clinically and histologically challenging. In this overview, after a consensus meeting in October 2016, we outline the histopathologic features and molecular mechanisms involved in the malignant transformation of neurofibromas. Nuclear atypia alone is generally insignificant. However, with atypia, loss of neurofibroma architecture, high cellularity, and/or mitotic activity >1/50 but <3/10 high-power fields, the findings are worrisome for malignancy. We propose the term "atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP)" for lesions displaying at least 2 of these features. This diagnosis should prompt additional sampling, clinical correlation, and possibly, expert pathology consultation. Currently, such tumors are diagnosed inconsistently as atypical neurofibroma or low-grade MPNST. Most MPNSTs arising from neurofibromas are high-grade sarcomas and pose little diagnostic difficulty, although rare nonnecrotic tumors with 3-9 mitoses/10 high-power fields can be recognized as low-grade variants. Although neurofibromas contain numerous S100 protein/SOX10-positive Schwann cells and CD34-positive fibroblasts, both components are reduced or absent in MPNST. Loss of p16/CDKN2A expression, elevated Ki67 labeling, and extensive nuclear p53 positivity are also features of MPNST that can to some degree already occur in atypical neurofibromatous neoplasms of uncertain biologic potential. Complete loss of trimethylated histone 3 lysine 27 expression is potentially more reliable, being immunohistochemically detectable in about half of MPNSTs. Correlated clinicopathological, radiologic, and genetic studies should increase our understanding of malignant transformation in neurofibromas, hopefully improving diagnosis and treatment soon.
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http://dx.doi.org/10.1016/j.humpath.2017.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628119PMC
September 2017

Pancreatic Neuroendocrine Tumor Secreting Vasoactive Intestinal Peptide and Dopamine With Pulmonary Emboli: A Case Report.

J Clin Endocrinol Metab 2016 10 1;101(10):3564-3567. Epub 2016 Sep 1.

Endocrine Oncology Branch (N.N., E.M.F., D.P., E.K.) and Laboratory of Pathology (M.M.Q.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

Context: The vasoactive intestinal peptide-secreting neuroendocrine tumor (VIPoma) is a very rare pancreatic tumor. We report the first case of a patient with VIPoma that co-secreted dopamine and had pulmonary emboli.

Case Description: A 67-year-old woman presented with 2 months of watery diarrhea, severe generalized weakness,6.8 kg of weight loss, a facial rash, and hypokalemia. Colonoscopy did not reveal the cause of the chronic diarrhea. Initial biochemical testing showed markedly elevated serum vasoactive intestinal peptide (VIP) and pancreatic polypeptide. Computed tomography scan of the abdomen and pelvis revealed a 5.4-cm distal pancreatic mass. Octreoscan showed an intense uptake in the area of the pancreatic mass. Incidental pulmonary emboli were found and treated. Additional biochemical testing revealed a markedly elevated urinary dopamine level. The patient received preoperative α-blockade and octreotide. She underwent a successful laparoscopic distal pancreatectomy. Postoperative urinary dopamine and pancreatic polypeptide were within normal limits. Serum VIP decreased by half but remained elevated. Pathology confirmed a grade 1 pancreatic neuroendocrine tumor without lymph node metastasis. The patient's symptoms resolved and no longer required octreotide. Metastatic workup including computed tomography, F18-fluorodeoxglucose positron emission tomography, and Ga68-DOTATATE scans were negative during 4 years of follow-up.

Conclusions: VIPoma is a rare subtype of pancreatic neuroendocrine tumor that can secrete dopamine and can be associated with thromboembolism.
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http://dx.doi.org/10.1210/jc.2016-2051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052354PMC
October 2016

Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors.

Gastroenterology 2016 07 18;151(1):140-51. Epub 2016 Mar 18.

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address:

Background & Aims: Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors believed to originate from enterochromaffin (EC) cells. Intestinal stem cell (ISC) are believed to contribute to the formation of SI-NETs, although little is known about tumor formation or development. We investigated the relationship between EC cells, ISCs, and SI-NETs.

Methods: We analyzed jejuno-ileal tissue specimens from 14 patients with familial SI-NETs enrolled in the Natural History of Familial Carcinoid Tumor study at the National Institutes of Health from January 2009 to December 2014. Frozen and paraffin-embedded tumor tissues of different stages and isolated crypts were analyzed by in situ hybridization and immunohistochemistry. Tumor clonality was assessed by analyses of mitochondrial DNA.

Results: We identified multifocal aberrant crypt-containing endocrine cell clusters (ACECs) that contain crypt EC cell microtumors in patients with familial SI-NETs. RNA in situ hybridization revealed expression of the EC cell and reserve stem cell genes TPH1, BMI1, HOPX, and LGR5(low), in the ACECs and more advanced extraepithelial tumor nests. This expression pattern resembled that of reserve EC cells that express reserve ISC genes; most reside at the +4 position in normal crypts. The presence of multifocal ACECs from separate tumors and in the macroscopic tumor-free mucosa indicated widespread, independent, multifocal tumorigenesis. Analyses of mitochondrial DNA confirmed the independent origin of the ACECs.

Conclusions: Familial SI-NETs originate from a subset of EC cells (reserve EC cells that express reserve ISC genes) via multifocal and polyclonal processes. Increasing our understanding of the role of these reserve EC cells in the genesis of multifocal SI-NETs could improve diagnostic and therapeutic strategies for this otherwise intractable disease.
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http://dx.doi.org/10.1053/j.gastro.2016.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578471PMC
July 2016

Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature.

Clin Infect Dis 2016 Apr 6;62(8):986-94. Epub 2016 Jan 6.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

Background: Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs).

Methods: STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed.

Results: We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only.

Conclusions: The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.
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http://dx.doi.org/10.1093/cid/civ1220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803104PMC
April 2016

Diagnosis of a growing radiation-induced skull lesion in a patient: an unusual scar.

J Neurosurg 2016 09 18;125(3):561-4. Epub 2015 Dec 18.

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke;

New lesions arising from within an area of previous irradiation often present a diagnostic dilemma, with new malignancy or metastasis of particular concern. The authors report a case of reactive fibroblast proliferation emerging from a previous radiation field and presenting as a growing lesion of the frontal and parietal skull. Following complete gross resection of the skull lesion and histopathological analysis, it was discovered that this lesion consisted of dense fibroblast proliferation with areas of osteonecrosis. This unusual reactive phenomenon offers a novel differential diagnosis for a new contrast-enhancing lesion in a region of previous radiation.
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http://dx.doi.org/10.3171/2015.7.JNS15989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5145258PMC
September 2016

Prospective evaluation and treatment of familial carcinoid small intestine neuroendocrine tumors (SI-NETs).

Surgery 2016 Jan 9;159(1):350-6. Epub 2015 Oct 9.

Digestive Diseases Branch, National Institute of Diabetes, Kidney and Digestive Diseases, National Institutes of Health, Bethesda, MD.

Background: The aim of this study was to prospectively screen patients with a positive family history of carcinoid small intestine neuroendocrine tumors (SI-NETs) to elucidate the benefits of early detection and operative intervention.

Methods: A single-center, prospective trial was conducted from 2008 to 2014 that evaluated patients with 2 or more blood relatives with carcinoid SI-NETs. All eligible patients were screened with urine/serum biochemistries and various imaging modalities. Operative intervention was elected in patients found to have at least 1 positive diagnostic study.

Results: Twenty-nine patients from 13 families had occult carcinoid SI-NETs (15 female, 14 male). Twenty-four of the 29 patients (83%) had multifocal disease found in either the distal jejunum or ileum. On average, 75.9 cm (range, 13-195) of bowel was resected in 1 segment. Three patients were found to have stage IV disease at operation. All stage I-IIIB patients who had R0 resections have remained disease-free, with a median follow-up of 35 months.

Conclusion: Familial carcinoid SI-NETs often are asymptomatic and can be diagnosed with aggressive screening. With early detection, there may be a window of opportunity for operative resection to change the natural history of this disease and even prove to be curative.
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http://dx.doi.org/10.1016/j.surg.2015.05.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858646PMC
January 2016

A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase.

Gastroenterology 2015 Jul 9;149(1):67-78. Epub 2015 Apr 9.

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address:

Background & Aims: Small intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer.

Methods: We performed a prospective study of 33 families with at least 2 cases of small intestinal carcinoids. Affected members were characterized clinically and asymptomatic relatives were screened and underwent exploratory laparotomy for suspected tumors. Disease-associated mutations were sought using linkage analysis, whole-exome sequencing, and copy number analyses of germline and tumor DNA collected from members of a single large family. We assessed expression of mutant protein, protein activity, and regulation of apoptosis and senescence in lymphoblasts derived from the cases.

Results: Familial and sporadic carcinoids are clinically indistinguishable except for the multiple synchronous primary tumors observed in most familial cases. Nearly 34% of asymptomatic relatives older than age 50 were found to have occult tumors; the tumors were cleared surgically from 87% of these individuals (20 of 23). Linkage analysis and whole-exome sequencing identified a germline 4-bp deletion in the gene inositol polyphosphate multikinase (IPMK), which truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and in 17 of 35 family members whose carcinoid status was unknown. Mutant IPMK had reduced kinase activity and nuclear localization, compared with the full-length protein. This reduced activation of p53 and increased cell survival.

Conclusions: We found that small intestinal carcinoids can occur as an inherited autosomal-dominant disease. The familial form is characterized by multiple synchronous primary tumors, which might account for 22%-35% of cases previously considered sporadic. Relatives of patients with familial carcinoids should be screened to detect curable early stage disease. IPMK haploinsufficiency promotes carcinoid tumorigenesis.
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http://dx.doi.org/10.1053/j.gastro.2015.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858647PMC
July 2015

Primary Aldosteronism and ARMC5 Variants.

J Clin Endocrinol Metab 2015 Jun 30;100(6):E900-9. Epub 2015 Mar 30.

Section on Endocrinology and Genetics (M.Z., P.X., F.R.F., A.B., A.G., M.H.S.-R., M.B., S.B.A., S.E., M.B.L., C.A.S.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Biostatistics and Clinical Epidemiology Service (N.S.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; Laboratory of Pathology (M.M.Q., M.M.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; Department of Pediatrics (A.H.), University Hospitals Case Medical Center, Rainbow Babies and Children's Hospital, Cleveland, Ohio 44106; Cardiovascular Disease Section (R.L., G.A., L.D., B.R.), Genomics of Metabolic, Cardiovascular, and Inflammatory Disease Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Department of Endocrinology, Metabolism, and Diabetes (A.D., S.Y.G., R.N., J.B.), Inserm Unit 1016, Centre National de la Recherche Scientifique UMR 8104, Institut Cochin, 75014 Paris, France; and Endocrine Oncology Branch (E.K.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

Context: Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia.

Objective: We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects.

Methods: Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods.

Results: We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023).

Conclusions: Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension.
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http://dx.doi.org/10.1210/jc.2014-4167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454793PMC
June 2015

Detection of insulinoma using (68)Gallium-DOTATATE PET/CT: a case report.

Gland Surg 2014 Nov;3(4):E1-5

1 Endocrine Oncology Branch, 2 Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA ; 3 Radiology Department, Warren Grant Magnusson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.

Insulinomas are the most common cause of endogenous hyperinsulinemic hypoglycemia in non-diabetic adults. They are most often benign, small and difficult to localize with current imaging techniques. This is of high importance, as complete surgical resection is the only curative treatment. Anatomic imaging, (111)In-pentetreotide scan and (68)Gallium-DOTATATE positron emission tomography/computed tomography (PET/CT) were compared in a patient with insulinoma. (68)Gallium-DOTATATE PET/CT and selective arterial calcium stimulation localized the insulinoma. At surgery, a tumor in the anterior aspect of the pancreatic body was found which confirmed the preoperative localization, and a 2.1 cm tumor was enucleated, World Health Organization (WHO) grade I insulinoma. The patient remains euglycemic and free of symptoms at last follow up. In conclusion, (68)Gallium-DOTATATE PET/CT imaging may be a useful adjunct localizing study for insulinomas. It is a non-invasive preoperative localization study that could guide surgical exploration for successful therapy.
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http://dx.doi.org/10.3978/j.issn.2227-684X.2014.10.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244512PMC
November 2014

miR30a inhibits LOX expression and anaplastic thyroid cancer progression.

Cancer Res 2015 Jan 8;75(2):367-77. Epub 2014 Dec 8.

Endocrine Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies, but its genetic drivers remain little understood. In this study, we report losses in expression of the miRNA miR30a, which is downregulated in ATC compared with differentiated thyroid cancer and normal tissue. miR30a downregulation was associated with advanced differentiated thyroid cancer and higher mortality. Mechanistically, we found miR30a decreased cellular invasion and migration, epithelial-mesenchymal transition marker levels, lysyl oxidase (LOX) expression, and metastatic capacity. LOX was identified as a direct target of miR30a that was overexpressed in ATC and associated with advanced differentiated thyroid cancer and higher mortality rate. Consistent with its role in other cancers, we found that LOX inhibited cell proliferation, cellular invasion, and migration and metastasis in vitro and in vivo. Together, our findings establish a critical functional role for miR30a downregulation in mediating LOX upregulation and thyroid cancer progression, with implications for LOX targeting as a rational therapeutic strategy in ATC.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986377PMC
January 2015

Hyperparathyroidism-jaw tumor syndrome: Results of operative management.

Surgery 2014 Dec 16;156(6):1315-24; discussion 1324-5. Epub 2014 Oct 16.

Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. Electronic address:

Background: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare, autosomal-dominant disease secondary to germline-inactivating mutations of the tumor suppressor gene HRPT2/CDC73. The aim of the present study was to determine the optimal operative approach to parathyroid disease in patients with HPT-JT.

Methods: A retrospective analysis of clinical and genetic features, parathyroid operative outcomes, and disease outcomes in 7 unrelated HPT-JT families.

Results: Seven families had 5 distinct germline HRPT2/CDC73 mutations. Sixteen affected family members (median age, 30.7 years) were diagnosed with primary hyperparathyroidism (PHPT). Fifteen of the 16 patients underwent preoperative tumor localization studies and uncomplicated bilateral neck exploration at initial operation; all were in biochemical remission at most recent follow-up. Of these patients, 31% had multiglandular involvement; 37.5% of the patients developed parathyroid carcinoma (median overall survival, 8.9 years; median follow-up, 7.4 years). Long-term follow-up showed that 20% of patients had recurrent PHPT.

Conclusion: Given the high risk of malignancy and multiglandular involvement in our cohort, we recommend bilateral neck exploration and en bloc resection of parathyroid tumors suspicious for cancer and life-long postoperative follow-up.
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http://dx.doi.org/10.1016/j.surg.2014.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255585PMC
December 2014

Ectopic adrenocorticotropic hormone and corticotropin-releasing hormone co-secreting tumors in children and adolescents causing cushing syndrome: a diagnostic dilemma and how to solve it.

J Clin Endocrinol Metab 2015 Jan;100(1):141-8

Section on Endocrinology and Genetics (A.S.K., J.B., M.F.K., C.L., M.B.L., C.A.S.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Section of Radiology and Imaging Sciences (G.Z.P., N.J.P.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; Laboratory of Pathology (M.M.Q., M.M.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; Thoracic and Gastrointestinal Oncology Branch (D.S.S.), Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; Endocrine Oncology Branch (E.K.), Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; Randall Children's Hospital at Legacy Emanuel (M.K.H.), Children's Diabetes and Endocrine Center, Portland, Oregon 97227; Department of Pediatrics (M.R.A., L.P.K., A.E.B.), Section of Diabetes and Endocrinology, Baylor College of Medicine, Houston, Texas 77030.

Context: Ectopic ACTH/CRH syndrome is a rare cause of Cushing syndrome (CS), especially in children. The localization, work-up, and management of ACTH/CRH-secreting tumors are discussed.

Setting: A retrospective study was conducted of patients under 21 years of age evaluated at the National Institutes of Health (NIH) for CS and diagnosed with ectopic ACTH/CRH-secreting tumors during the period 2009-2014.

Patients: Seven patients with ectopic ACTH/CRH CS are included in this study with a median age 13.6 years (range 1-21), and 3 are female.

Measurements: Clinical, biochemical, radiological features, treatment, and histological findings are described.

Results: Seven patients were found to have ACTH/CRH-secreting tumors, all with neuroendocrine features. The site of the primary lesion varied: pancreas (3), thymus (2), liver (1), right lower pulmonary lobe (1). PATIENTS underwent biochemical evaluation for CS, including diurnal serum cortisol and ACTH levels, urinary free cortisol levels (UFC), and CRH stimulation tests. All patients underwent radiological investigations including MRI, CT, and PET scan; imaging with octreotide and 68 gallium DOTATATE scans were performed in individual cases. Five patients underwent inferior petrosal sinus sampling; 4 patients had sampling for ACTH and CRH levels from additional sites. Three patients underwent trans-sphenoidal surgery (TSS), and 3 patients required bilateral adrenalectomy. Three patients (43%) died due to metastatic disease, demonstrating the high mortality rate. One of the unique findings in these seven patients is that in each case, their neuroendocrine tumors were ultimately proven to be co-secreting ACTH and CRH. This explains the enigmatic presentation, in which 3 patients initially thought to have Cushing's disease (CD) with corresponding pituitary hyperplasia underwent TSS prior to the correct localization of the causative tumor.

Conclusions: Ectopic ACTH/CRH co-secreting tumors are extremely rare in children and adolescents. The diagnosis of this condition is frequently missed and is sometimes confused with CD due to the effect of CRH on the pituitary.
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http://dx.doi.org/10.1210/jc.2014-2945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283025PMC
January 2015

Multifocal dysembryoplastic neuroepithelial tumours associated with refractory epilepsy.

Epileptic Disord 2014 Sep;16(3):328-32

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda.

Dysembryoplastic neuroepithelial tumours (DNET) are a common cause of tumour-associated epilepsy, and are usually located in the temporal lobes. We present a case of multifocal DNETs in both infra- and supra-tentorial locations, in a 23-year-old man with a coincident Type I Chiari malformation, presenting with medically refractory focal seizures. The extensive anatomical distribution of the lesions suggests a genetic component in their tumourigenesis.
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http://dx.doi.org/10.1684/epd.2014.0680DOI Listing
September 2014

Von hippel-lindau disease associated pulmonary carcinoid with cranial metastasis.

J Clin Endocrinol Metab 2014 Aug 30;99(8):2633-6. Epub 2014 May 30.

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (C.Z., A.I.Y., C.Y., C.L.N., P.C., J.D.H., Z.Z., K.A.Z.), and Laboratory of Pathology, National Cancer Institute (L.V., S.M., L.S., Z.A., S.D.P., A.G., M.M.Q.), National Institutes of Health, Bethesda, Maryland 20892; and Department of Orthopedics (C.Z.), Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China.

Context: Carcinoids have rarely been described in von Hippel-Lindau (VHL) disease.

Objective: We describe the first reported case of a patient with VHL who developed a pulmonary carcinoid that subsequently metastasized to a pre-existent cranial hemangioblastoma.

Results: Histological and immunohistochemical features of the metastatic lesion were similar to the primary carcinoid. Both lesions demonstrated heterozygous VHL gene deletions with fluorescence in situ hybridization analysis.

Conclusions: This case provides direct molecular genetic evidence of an association between VHL and carcinoids.
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http://dx.doi.org/10.1210/jc.2014-1732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121022PMC
August 2014

Analysis of IGF and IGFBP as prognostic serum biomarkers for adrenocortical carcinoma.

Ann Surg Oncol 2014 Oct 16;21(11):3541-7. Epub 2014 May 16.

Endocrine Oncology Branch, National Cancer Institute, NIH, Bethesda, MD, USA,

Background: Adrenocortical carcinoma (ACC) lacks diagnostic and prognostic biomarkers to guide treatment. A consistently dysregulated pathway in ACC is the IGF signaling pathway, specifically overexpression of IGF2, IGF-I-receptor, and IGFBP2. The objective of this study was to perform a comprehensive analysis of serum IGF and IGFBP levels and to determine their utility as diagnostic and prognostic biomarkers in ACC.

Methods: Preoperative serum samples from 53 patients who underwent surgery for adrenocortical adenomas, 3 patients who underwent initial surgery for ACC, 16 patients who underwent reoperative surgery for ACC, and 5 healthy volunteer controls were analyzed. The serum concentration of IGF1, IGF2, IGFBP1, IGFBP2, and IGFBP3 was determined by enzyme-linked immunosorbent assay.

Results: No difference in the levels of IGF2 (p = .231) and IGFBP2 (p = .511) was observed between patients with ACC, benign adrenocortical tumors, and healthy volunteers. IGF1, IGFBP1, and IGFBP3 levels were not detected. High IGFBP2 levels were associated with better overall survival (OS) (p = .001) and showed a trend toward better abdominal progression-free (APFS) survival (p = .070) in patients with ACC. A subanalysis of patients undergoing reoperation for recurrent ACC showed better OS with high levels of IGFBP2 (p = .003) and a trend toward better APFS (p = .107). There was no significant difference in IGF2 and IGFBP2 levels by extent of disease.

Conclusions: IGF2 and IGFBP2 are not elevated in the serum of patients with ACC compared with patients with benign neoplasms and healthy volunteers. Elevated serum IGFBP2 is associated with better survival in patients with ACC and those undergoing reoperative surgery for recurrent ACC.
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http://dx.doi.org/10.1245/s10434-014-3768-5DOI Listing
October 2014

Early-onset stroke and vasculopathy associated with mutations in ADA2.

N Engl J Med 2014 Mar 19;370(10):911-20. Epub 2014 Feb 19.

The authors' affiliations are listed in the Appendix.

Background: We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood.

Methods: We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells.

Results: All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia - phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers.

Conclusions: Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.).
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http://dx.doi.org/10.1056/NEJMoa1307361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4193683PMC
March 2014