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1.
Ann Surg Oncol ; 2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33586069

RESUMO

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy, and many prognostic factors that influence survival remain undefined. Individually, the GRAS (Grade, Resection status, Age, and Symptoms of hormone hypersecretion) parameters have demonstrated their prognostic value in ACC. This study aimed to assess the value of a cumulative GRAS score as a prognostic indicator after ACC resection. METHODS: A retrospective cohort study of adult patients who underwent surgical resection for ACC between 1993 and 2014 was performed using the United States Adrenocortical Carcinoma Group (US-ACCG) database. A sum GRAS score was calculated for each patient by adding one point each when the criteria were met for tumor grade (Weiss criteria ≥ 3 or Ki67 ≥ 20%), resection status (micro- or macroscopically positive margin), age (≥ 50 years), and preoperative symptoms of hormone hypersecretion (present). Overall survival (OS) and disease-free survival (DFS) by cumulative GRAS score were analyzed by the Kaplan-Meier method and log-rank test. RESULTS: Of the 265 patients in the US-ACCG database, 243 (92%) had sufficient data available to calculate a cumulative GRAS score and were included in this analysis. The 265 patients comprised 23 patients (10%) with a GRAS of 0, 52 patients (21%) with a GRAS of 1, 92 patients (38%) with a GRAS of 2, 63 patients (26%) with a GRAS of 3, and 13 patients (5%) with a GRAS of 4. An increasing GRAS score was associated with shortened OS (p < 0.01) and DFS (p < 0.01) after index resection. CONCLUSION: In this retrospective analysis, the cumulative GRAS score effectively stratified OS and DFS after index resection for ACC. Further prospective analysis is required to validate the cumulative GRAS score as a prognostic indicator for clinical use.

2.
Cancer Med ; 10(3): 1084-1090, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33449450

RESUMO

BACKGROUND: 18 F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) positive (PET+) cytologically indeterminate thyroid nodules (ITNs) have variable cancer risk in the literature. The benign call rate (BCR) of Afirma Gene Classifier (Gene Expression Classifier, GEC, or Genome Sequence Classifier, GSC) in (PET +) ITNs is unknown. METHODS: This is a retrospective study at our institution of all patients with (PET+) ITNs (Bethesda III/IV) from 1 January 2010 to 21 May 2019 who underwent Afirma testing and/or surgery or repeat FNA with benign cytology. RESULTS: Forty-five (PET+) ITNs were identified: 31 Afirma-tested (GEC = 20, GSC = 11) and 14 either underwent surgery (n = 13) or repeat FNA (Benign cytology) (n = 1) without Afirma. The prevalence of cancer and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) including only resected nodules and ITN with repeat benign FNA (n = 33) was 36.4% (12/33). Excluding all Afirma "suspicious" non-resected ITNs and assuming all Afirma "benign" ITNs were truly benign, that prevalence was 28.6% (12/42). The BCR with GSC was 64% compared to 25% with GEC (p = 0.056). Combining GSC/GEC-tested ITNs, the BCR was higher in ITNs demonstrating low/very low-risk sonographic pattern by the American Thyroid Association (ATA) classification and ITNs scoring <4 by the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR-TI-RADS) than ITNs with higher sonographic pattern/score (p = 0.025). CONCLUSIONS: The prevalence of cancer/NIFTP in (PET+) ITNs was 28.6-36.4% depending on the method of calculation. The BCR of Afirma GSC was 64%. Combining Afirma GEC/GSC-tested ITNs, BCR was higher in ITNs with a lower risk sonographic pattern.

3.
J Clin Endocrinol Metab ; 105(11)2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32772084

RESUMO

BACKGROUND: Most cytologically indeterminate thyroid nodules (ITNs) with benign molecular testing are not surgically removed. The data on clinical outcomes of these nodules are limited. METHODS: We retrospectively analyzed all ITNs where molecular testing was performed either with the Afirma gene expression classifier or Afirma gene sequencing classifier between 2011 and 2018 at a single institution. RESULTS: Thirty-eight out of 289 molecularly benign ITNs were ultimately resected. The most common reason for surgery was compressive symptoms (39%). In multivariable modeling, patients aged <40 years, nodules ≥3 cm, presence of an Afirma suspicious nodule other than the index nodule, and compressive symptoms were associated with higher surgery rates with hazard ratios for surgery of 3.5 (P < 0.001), 3.2 (P < 0.001), 16.8 (P < 0.001), and 7.31 (P < 0.001), respectively. Of resected nodules, 5 were malignant. False-negative rate (FNR) was 1.7%, presuming all unresected nodules were truly benign and 13.2% restricting analysis to resected cases. The FNR was significantly higher in nodules with a high-risk sonographic appearance for cancer (American Thyroid Association high-risk classification and American College of Radiology Thyroid Imaging Reporting and Data Systems score of 5) compared with nodules with all other sonographic categories (11.8% vs 1.1%; P = 0.03 and 11.1% vs 1.1%; P = 0.02, respectively). CONCLUSIONS: Younger age, larger nodule size, presence of an Afirma suspicious nodule other than the index nodule, and compressive symptoms were associated with a higher rate of surgery. The FNR of benign Afirma was significantly higher in nodules with high-risk sonographic features.

4.
J Surg Res ; 256: 458-467, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32798993

RESUMO

BACKGROUND: Despite the advances in treatment of differentiated thyroid cancer (DTC), predicting prognosis remains a challenge. Immune cells in the tumor microenvironment may provide an insight to predicting recurrence. Therefore, the objective of this study was to investigate the association of tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) with recurrence in DTC and to identify serum cytokines that correlate with the presence of these immune cells in the tumor. MATERIALS AND METHODS: Forty-two DTC tissues from our institutional neoplasia repository were stained for immunohistochemistry markers for TAMs and TANs. In addition, cytokine levels were analyzed from these patients from preoperative blood samples. TAM and TAN staining were compared with clinical data and serum cytokine levels. RESULTS: Neither TAM nor TAN scores alone correlated with tumor size, the presence of lymph node metastases, multifocal tumors, lymphovascular or capsular invasion, or the presence of BRAFV600E mutation (all P > 0.05). There was no association with recurrence-free survival (RFS) in TAN density (mean RFS, 169.1 versus 148.1 mo, P = 0.23) or TAM density alone (mean RFS, 121.3 versus 205.2 mo, P = 0.54). However, when scoring from both markers were combined, patients with high TAM density and TAN negative scores had significantly lower RFS (mean RFS, 50.7 versus 187.3 mo, P = 0.04) compared with the remaining cohort. Patients with high TAM/negative TAN tumors had significantly lower serum levels of interleukin 12p70, interleukin 8, tumor necrosis factor alpha, and tumor necrosis factor beta. CONCLUSIONS: In DTCs, high density of TAMs in the absence of TANs is associated with worse outcome. Assessment of multiple immune cell types and serum cytokines may predict outcomes in DTC.

5.
Ann Surg Oncol ; 27(5): 1329-1337, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32112212

RESUMO

This first part of a two-part review of pheochromocytoma and paragangliomas (PPGLs) addresses clinical presentation, diagnosis, management, treatment, and outcomes. In this first part, the epidemiology, prevalence, genetic etiology, clinical presentation, and biochemical and radiologic workup are discussed. In particular, recent advances in the genetics underlying PPGLs and the recommendation for genetic testing of all patients with PPGL are emphasized. Finally, the newer imaging methods for evaluating of PPGLs are discussed and highlighted.

6.
Ann Surg Oncol ; 27(5): 1338-1347, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32112213

RESUMO

This is the second part of a two-part review on pheochromocytoma and paragangliomas (PPGLs). In this part, perioperative management, including preoperative preparation, intraoperative, and postoperative interventions are reviewed. Current data on outcomes following resection are presented, including outcomes after cortical-sparing adrenalectomy for bilateral adrenal disease. In addition, pathological features of malignancy, surveillance considerations, and the management of advanced disease are also discussed.

7.
Surgery ; 167(2): 352-357, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31272813

RESUMO

BACKGROUND: Adrenocortical carcinoma is a rare, aggressive cancer. We compared features of patients who underwent synchronous versus metachronous metastasectomy. METHODS: Adult patients who underwent resection for metastatic adrenocortical carcinoma from 1993 to 2014 at 13 institutions of the US adrenocortical carcinoma group were analyzed retrospectively. Patients were categorized as synchronous if they underwent metastasectomy at the index adrenalectomy or metachronous if they underwent resection after recurrence of the disease. Factors associated with overall survival were assessed by univariate analysis. RESULTS: In the study, 84 patients with adrenocortical carcinoma underwent metastasectomy; 26 (31%) were synchronous and 58 (69%) were metachronous. Demographics were similar between groups. The synchronous group had more T4 tumors at the index resection (42 vs 3%, P < .001). The metachronous group had prolonged median survival after the index resection (86.3 vs 17.3 months, P < .001) and metastasectomy (36.9 vs 17.3 months, P = .007). Synchronous patients with R0 resections had improved survival compared to patients with R1/2 resections (P = .008). Margin status at metachronous metastasectomy was not associated with survival (P = .452). CONCLUSION: Select patients with metastatic adrenocortical carcinoma may benefit from metastasectomy. Patients with metachronous metastasectomy have a more durable survival benefit than those undergoing synchronous metastasectomy. This study highlights need for future studies examining differences in tumor biology that could explain outcome disparities in these distinct patient populations.


Assuntos
Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/cirurgia , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/secundário , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Estados Unidos/epidemiologia
8.
J Am Coll Surg ; 229(6): 596-608.e3, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31562910

RESUMO

BACKGROUND: Near infrared autofluorescence (NIRAF) can guide intraoperative parathyroid gland (PG) identification. NIRAF detection devices typically rely on imaging and fiber probe-based approaches. Imaging modalities provide NIRAF pictures on adjacent display monitors, and fiber probe-based systems measure tissue NIRAF and provide real-time quantitative information to objectively aid PG identification. Both device types recently gained FDA approval for PG identification but have never been compared directly. STUDY DESIGN: Patients undergoing thyroidectomy and/or parathyroidectomy were recruited prospectively. Target tissues were intraoperatively visualized with PDE-Neo II (imaging-based) and concurrently assessed with PTeye (fiber probe-based). For PDE-Neo II, NIRAF images were collected from in situ or excised tissues, alongside the surgeon's interpretation of visualized tissues, and retrospectively analyzed in a blinded fashion. The PTeye was concomitantly used to record NIRAF intensities and ratios from the same tissues in real time. RESULTS: Twenty patients were enrolled for concurrent evaluation with both systems, which included 33 PGs and 19 nonparathyroid sites. NIRAF imaging demonstrated 90.9% sensitivity, 73.7% specificity, and 84.6% accuracy for PG identification when interpreted in real time by the surgeon compared with 81.8% sensitivity, 73.7% specificity, and 78.8% accuracy where images were quantitatively analyzed post hoc by an independent observer. In parallel, NIRAF detection with PTeye yielded 97.0% sensitivity, 84.2% specificity, and 92.3% accuracy in real time for the same specimens. CONCLUSIONS: Both NIRAF-based systems were beneficial for identifying PGs intraoperatively. Although NIRAF imaging provides valuable spatial information to localize PGs, NIRAF detection with fiber probe provides real-time quantitative information to identify PGs in presence of ambient room lights.


Assuntos
Imagem Óptica/métodos , Glândulas Paratireoides/diagnóstico por imagem , Paratireoidectomia/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Cirurgia Assistida por Computador/métodos , Tireoidectomia/métodos , Adulto , Feminino , Seguimentos , Humanos , Masculino , Microcirurgia/métodos , Pessoa de Meia-Idade , Glândulas Paratireoides/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos
9.
Horm Cancer ; 10(4-6): 161-167, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31468469

RESUMO

Adrenocortical carcinoma (ACC) is a rare malignancy with limited data to guide the management of metastatic disease. The optimal treatment strategies and outcomes of patients with metastatic ACC remain areas of active interest. We retrospectively reviewed patients with ACC who were treated with systemic therapy between January 1997 and October 2016 at The Ohio State University Comprehensive Cancer Center. Kaplan-Meier and Cox proportional hazards regression models were used for survival analysis. We identified 65 patients diagnosed with ACC during the given time period, and 36 patients received systemic therapy for distant metastatic disease. Median age at diagnosis was 50 (range 28-87). Median overall survival (OS) from time of diagnosis of ACC was 27 months (95% CI 19.6-39.3), and median OS from time of systemic treatment for metastatic disease was 18.7 months (95% CI 9.3-26.0). Clinical characteristics at time of initiation of systemic therapy were assessed, and presence of bone metastases (p = 0.66), ascites (p = 0.19), lung metastases (p = 0.12), liver metastases (p = 0.47), as well as hormonal activity of tumor (p = 0.19), were not prognostic for survival. Six patients with liver metastases treated with systemic therapy who received liver-directed therapy with either transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT) had longer survival than those who did not (p = 0.011). Our data expands the knowledge of clinical characteristics and outcomes of patients with ACC and suggests a possible role for incorporating liver-directed therapies for patients with hepatic metastases.


Assuntos
Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/mortalidade , Metástase Neoplásica/terapia , Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/terapia , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida
10.
Artigo em Inglês | MEDLINE | ID: mdl-31369053

RESUMO

Importance: Intrinsic near-infrared (NIR) autofluorescence of the parathyroid gland enables intraoperative gland identification without the need for contrast agent injection. However, whether real-time autofluorescence imaging is useful in patients with multiple endocrine neoplasia type 1 (MEN1) and primary hyperparathyroidism is unknown. Objective: To compare quantified intraoperative parathyroid autofluorescence imaging results for patients with MEN1-associated vs those with non-MEN1 sporadic primary hyperparathyroidism. Design, Setting, and Participants: A retrospective analysis of prospectively collected data on a cohort of 71 consecutive patients undergoing surgery for primary hyperparathyroidism by 2 experienced endocrine surgeons between June 1, 2017, and July 31, 2018, was conducted. Intraoperative imaging was performed with a handheld NIR autofluorescence device and images were captured for analysis. Post hoc blinded imaging analysis was conducted with Image J software to quantify representative areas of greatest autofluorescence from the parathyroid, thyroid, and adjacent soft tissue. Main Outcomes and Measures: Primary end points were parathyroid autofluorescence and background thyroid and soft tissue autofluorescence, reported as median values with interquartile ranges. Rates of false-negative (lack of significant parathyroid gland autofluorescence compared with background autofluorescence, defined as parathyroid autofluorescence-background autofluorescence ratio <1.10) and false-positive autofluorescence (aberrant autofluorescence of nonparathyroid tissue confirmed by pathologic testing) were analyzed. Results: Of the 71 consecutive patients with primary hyperparathyroidism who underwent parathyroidectomy during the study period, 6 patients had genetically or clinically diagnosed MEN1 and 65 had sporadic non-MEN1 hyperparathyroidism. Most patients were women (MEN1: 4 [67%]; non-MEN1: 51 [78%]). Median (interquartile range) age was 49.0 (38.0-53.8) years in the MEN1 cohort and 61.0 (54.0-67.0) years in the non-MEN1 cohort. No clinically significant differences in serum preoperative parathyroid hormone level or parathyroid gland size or weight on pathologic examination were observed between the 2 cohorts. The median absolute value of in situ parathyroid autofluorescence was significantly lower in the MEN1 cohort than the non-MEN1 cohort (54.4 vs 74.3; Hedges g = -1.03; 95% CI, -1.89 to -0.17), as was the ratio of parathyroid to background autofluorescence (1.08 vs 1.59; g = -1.59; 95% CI, -2.23 to -0.96). Three patients (50%) with MEN1 had false-negative nonfluorescent parathyroid adenomas vs 6 patients (9%) without MEN1. Nonparathyroid fibroadipose tissue of patients with MEN1 exhibited greater background autofluorescence, leading to high false-positive rates (5 of 6 patients [83%]) vs only 3 of 65 (5%) false-positive autofluorescence nonparathyroid specimens among patients without MEN1. Conclusions and Relevance: Intraoperative identification of parathyroid glands using their autofluorescence by real-time NIR imaging appears to have utility in patients with primary hyperparathyroidism. In this initial cohort of patients with MEN1, decreased parathyroid autofluorescence and increased background autofluorescence of nonparathyroid tissue may be associated with high rates of false-negative and false-positive fluorescence, potentially limiting the utility of this adjunct in this specific subset of patients.

11.
Thyroid ; 29(8): 1115-1124, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31154940

RESUMO

Background: The Afirma Gene Expression Classifier (GEC) has been used to further characterize cytologically indeterminate (cyto-I) thyroid nodules into either benign or suspicious categories. However, its relatively low positive predictive value (PPV) limited its use as a classifier for patients with suspicious results. The Afirma Gene Sequencing Classifier (GSC) was developed to improve PPV while maintaining a high negative predictive value (NPV), yet real-world assessment of its performance is lacking. Methods: We analyzed all patients who had cyto-I nodules and molecular testing with either GEC or GSC between 2011 and 2018 at a single academic medical center. Clinical information was obtained for 343 GEC-tested nodules and 164 GSC-tested nodules. Results: The GSC had a statistically significant higher benign call rate (76.2% vs. 48.1%, p < 0.001), PPV (60.0% vs. 33.3%, p = 0.01), and specificity (94.3% vs. 61.4%, p < 0.001) than the GEC. Improvement was statistically significant in both Bethesda III and Bethesda IV nodules. In particular, the benign call rate of GSC was significantly higher in nodules with Hürthle cell changes (88.8% vs. 25.7%, p < 0.01). The rate of surgical intervention in the indeterminate nodule cohort has decreased by 66.4% since switching to the GSC; 52.5% of indeterminate nodules went to surgery while using the GEC compared with 17.6% with the GSC (p < 0.001). This reduction was statistically significant in nodules with Bethesda III diagnoses, demonstrating a 70.9% decrease (GEC 51.3% vs. GSC 14.9%, p < 0.001), and in nodules with Bethesda IV cytology, a 39.2% decrease was noted (GEC 54.8% vs. GSC 33.3%, p = 0.003). Conclusions: Data from a single academic tertiary center show an improved specificity and PPV while maintaining high sensitivity and NPV for GSC compared with GEC. A statistically significant increase in benign call rates was observed in GSC compared with GEC, likely indicating fewer false positive results. After implementation of GSC, surgical interventions have been reduced by 68%.


Assuntos
Perfilação da Expressão Gênica , Análise de Sequência de DNA , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/genética , Adenocarcinoma Folicular/diagnóstico , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patologia , Adenoma Oxífilo/diagnóstico , Adenoma Oxífilo/genética , Adenoma Oxífilo/patologia , Adulto , Idoso , Biópsia por Agulha Fina , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/patologia
12.
Thyroid ; 29(4): 523-529, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30747051

RESUMO

BACKGROUND: Inactivation of DNA mismatch repair (MMR) and the resulting microsatellite instability (MSI) are frequently observed in endometrial, stomach, and colorectal cancers, as well as more rarely in other solid tumor types. The prevalence of MSI in thyroid cancer has not been explored in depth, although recent studies utilizing data from large cancer sequencing efforts such as The Cancer Genome Atlas indicate that MSI is absent or at least very rare in the most common and most well studied histologic subtype, papillary thyroid carcinoma. This study aimed to determine the prevalence of MSI in thyroid cancer by using a large series comprising all major histological subtypes. METHODS: A total of 485 thyroid cancer patients were screened for MSI/MMR deficiency, including all major histologic subtypes (195 papillary thyroid carcinoma, 156 follicular thyroid carcinoma [FTC], 50 anaplastic thyroid carcinoma, 65 medullary thyroid carcinoma, and 17 poorly differentiated thyroid carcinomas) by using a combination of polymerase chain reaction-based detection, immunohistochemistry, and next-generation sequencing. RESULTS: A total of four tumors were MSI-high and had loss of MMR protein expression, all of which were from FTC patients. Whole-exome sequencing was performed on two MSI-high FTCs and revealed a hemizygous loss of function mutation in MSH2 in one tumor. CONCLUSIONS: Based on these data, it is estimated that the overall prevalence of MSI in FTC is 2.5%, and MSI is either entirely absent or rare in other histology subtypes of thyroid carcinoma. These findings highlight the importance of testing for MSI in FTC.


Assuntos
Adenocarcinoma Folicular/genética , Biomarcadores Tumorais/genética , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Proteína 2 Homóloga a MutS/genética , Neoplasias da Glândula Tireoide/genética , Adenocarcinoma Folicular/patologia , Predisposição Genética para Doença , Hemizigoto , Humanos , Perda de Heterozigosidade , Mutação , Fenótipo , Fatores de Risco , Neoplasias da Glândula Tireoide/patologia
13.
Ann Surg Oncol ; 26(4): 1142-1148, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30675703

RESUMO

BACKGROUND: Intrinsic near-infrared (NIR) autofluorescence of the parathyroid gland may improve intraoperative gland identification without the need for contrast agent injection. Compared with patients undergoing surgery for thyroid disease, identification of pathologic parathyroid tissue in patients with hyperparathyroidism is essential. This study analyzed the utility of a novel real-time autofluorescence imaging system in patients with primary hyperparathyroidism enrolled in a prospective feasibility clinical trial. METHODS: Data on patients undergoing surgery for primary hyperparathyroidism by two experienced endocrine surgeons were prospectively collected. Intraoperative imaging was performed with a handheld NIR device, and images were captured for analysis. The collected data included the surgeon's confidence in parathyroid identification, both with ambient light and use of NIR imaging, as well as how the imaging affected the surgical procedure. Images were quantified by Image J software, with autofluorescence reported as mean values ± SD. RESULTS: From 2017 to 2018, 59 consecutive patients with a diagnosis of primary hyperparathyroidism underwent resection of 69 parathyroid glands. Use of NIR imaging increased the intraoperative confidence of parathyroid identification (on a scale of 0-5) from an average of 4.1 to an average of 4.4 (+0.3, p = 0.003), all of which were confirmed pathologically. The addition of autofluorescence helped to identify the parathyroid gland in 12 patients (20%), and to rule out other soft tissue as not parathyroid in an additional 9 patients (15%). The mean autofluorescence for the parathyroid in situ (75.9 ± 21.3) was significantly greater than that for the thyroid (61.1 ± 17.4) or soft tissue (53.3 ± 19.2) (p < 0.001 for both). The mean absolute difference in parathyroid versus background thyroid autofluorescence was +15.2 (range, 2.4-53.1). CONCLUSION: This is the first prospective trial to examine the utility of parathyroid autofluorescence for identifying glands exclusively in patients with parathyroid disease. Intraoperative identification and localization of parathyroid glands by real-time, NIR imaging using their intrinsic autofluorescence is feasible and may provide a useful adjunct during parathyroid surgery.


Assuntos
Hiperparatireoidismo Primário/diagnóstico por imagem , Cuidados Intraoperatórios , Imagem Óptica/métodos , Glândulas Paratireoides/diagnóstico por imagem , Paratireoidectomia/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Cirurgia Assistida por Computador/métodos , Idoso , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Hiperparatireoidismo Primário/cirurgia , Masculino , Pessoa de Meia-Idade , Glândulas Paratireoides/cirurgia , Prognóstico , Estudos Prospectivos
14.
Int J Cardiol ; 275: 114-119, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30384979

RESUMO

BACKGROUND: Myocarditis may be self-limited but has been identified as an important contributor to downstream cardiomyopathy. Aldosterone mediates myocardial damage in various conditions, but has not been considered specifically as a therapeutic target for inflammatory damage in acute myocarditis. We sought to demonstrate local aldosterone synthesis in human myocardium affected by acute myocarditis. METHODS: We evaluated myocardial samples obtained via endomyocardial biopsy (EMB) for expression of CYP11B2, the final and key enzyme for aldosterone synthesis, from patients with acute myocarditis and from stable heart transplant recipients with no evidence of rejection as negative controls. Excised adrenal glands from patients with aldosterone-secreting adenomas were used as positive controls. An experienced cardiovascular pathologist blinded to clinical information rated CYP11B2 stains as negative, positive, or borderline, also recording location of any CYP11B2-positivity. RESULTS: Sixteen patients' EMB samples showing definite acute myocarditis were identified (50% female). CYP11B2 was positive in 13/16 cases (81%), typically showing diffuse intracardiomyocyte cytoplasmic staining, vs. 2/16 borderline stains in transplant controls (p < 0.001 myocarditis vs. negative controls). All 3 adrenalectomy samples stained positive for CYP11B2 (diffuse intracellular staining). Importantly, no myocarditis or transplant patients were on aldosterone antagonist therapy at the time of biopsy. CONCLUSIONS: In this proof-of-concept study, myocardium from patients with acute myocarditis demonstrates evidence and high prevalence of local aldosterone synthesis by immunohistochemistry that showed high accuracy, specificity, and sensitivity. Aldosterone warrants consideration as a specific target for therapy in patients with myocardial damage due to inflammation towards strategies that reduce downstream complications.


Assuntos
Aldosterona/biossíntese , Miocardite/metabolismo , Miocárdio/metabolismo , Doença Aguda , Adulto , Biomarcadores/metabolismo , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Miocardite/patologia , Miocárdio/patologia
16.
Thyroid ; 28(11): 1517-1531, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30084742

RESUMO

BACKGROUND: Patients undergoing thyroidectomy may have inadvertent damage or removal of the parathyroid gland(s) due to difficulty in real-time parathyroid identification. Near-infrared autofluorescence (NIRAF) has been demonstrated as a label-free modality for intraoperative parathyroid identification with high accuracy. This study presents the translation of that approach into a user-friendly clinical prototype for rapid intraoperative guidance in parathyroid identification. METHODS: A laboratory (lab)-built spectroscopy system that measures NIRAF in tissue was evaluated for identifying parathyroid glands in vivo across 162 patients undergoing thyroidectomy and/or parathyroidectomy. Based on these results, a clinical prototype called PTeye was designed with a user-friendly interface and subsequently investigated in 35 patients. The performance of the lab-built system and the clinical prototype were concurrently compared side by side by a single user with 20 patients in each group. The influence of (i) intrapatient and interpatient variability of NIRAF in thyroid and parathyroid glands and (ii) thyroid and parathyroid pathology on intraoperative parathyroid identification were investigated. The effect of blood on NIRAF intensity of parathyroid and thyroid was tested ex vivo with the PTeye system to assess if a hemorrhagic surgical field would affect parathyroid identification. Accuracy of both systems were determined by correlating the acquired data with either visual confirmation by a surgeon for unexcised parathyroid glands or histology reports for excised parathyroid glands. RESULTS: The overall accuracy of the lab-built system in guiding parathyroid identification was 92.5%, while the PTeye system achieved an accuracy of 96.1%. Unlike the lab-built system, the PTeye could guide parathyroid identification even as the operating room lights remained on and required only 25% of the laser power used by the lab-built setup. Parathyroid glands had elevated NIRAF intensity compared to thyroid and other neck tissues, regardless of thyroid or parathyroid pathology. Blood did not seem to affect tissue NIRAF measurements obtained with both systems. CONCLUSION: In this study, the clinical prototype PTeye demonstrated high accuracy for label-free intraoperative parathyroid identification. The intuitive interface of the PTeye that can guide in identifying parathyroid tissue in the presence of ambient room lights suggests that it is a reliable and easy-to-use tool for surgical personnel.


Assuntos
Complicações Intraoperatórias/prevenção & controle , Glândulas Paratireoides/lesões , Glândula Tireoide/cirurgia , Tireoidectomia/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Complicações Intraoperatórias/etiologia , Masculino , Pessoa de Meia-Idade , Paratireoidectomia , Adulto Jovem
17.
Ann Surg Oncol ; 25(12): 3711-3717, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30076554

RESUMO

BACKGROUND: Injury to the thoracic duct (TD) is the most common complication after a left lateral neck dissection, and it carries a high degree of morbidity. Currently, no routine diagnostic imaging is used to assist with TD identification intraoperatively. This report describes the first clinical experience with lymphangiography using indocyanine green (ICG) during lateral neck dissections. METHODS: In six patients undergoing left lateral neck dissection (levels 2-4) for either thyroid cancer or melanoma, 2.5-5 mg of ICG was injected in the dorsum of the left foot 15 min before imaging. Intraoperative imaging was performed with a hand-held near infrared (NIR) camera (Hamamatsu, PDE-Neo, Hamamatsu City, Japan). RESULTS: In five patients, the TD was visualized using NIR fluorescence, with a time of 15-90 min from injection to identification. Imaging was optimized by positioning the camera at the angle of the mandible and pointing into the space below the clavicle. No adverse reactions from the ICG injection occurred, and the time required for imaging was 5-10 min. No intraoperative TD injury was identified, and no chyle leak occurred postoperatively. For the one patient in whom the TD was not identified, it is unclear whether this was related to the timing of the injection or to duct obliteration from a prior dissection. CONCLUSION: This is the first described application of ICG lymphangiography to identify the thoracic duct during left lateral neck dissection. Identification of TD with ICG is technically feasible, simple to perform with NIR imaging, and safe, making it a potential important adjunct for the surgeon.


Assuntos
Corantes/metabolismo , Verde de Indocianina/metabolismo , Excisão de Linfonodo , Linfonodos/cirurgia , Melanoma/cirurgia , Ducto Torácico/patologia , Neoplasias da Glândula Tireoide/cirurgia , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Linfonodos/patologia , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Ducto Torácico/metabolismo , Neoplasias da Glândula Tireoide/patologia
18.
Genet Med ; 20(9): 927-935, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29300379

RESUMO

PURPOSE: To identify and characterize the functional variants, regulatory gene networks, and potential binding targets of SMAD3 in the 15q22 thyroid cancer risk locus. METHODS: We performed linkage disequilibrium (LD) and haplotype analyses to fine map the 15q22 locus. Luciferase reporter assays were applied to evaluate the regulatory effects of the candidate variants. Knockdown by small interfering RNA, microarray analysis, chromatin immunoprecipitation (ChIP) and quantitative real-time polymerase chain reaction assays were performed to reveal the regulatory gene network and identify its binding targets. RESULTS: We report a 25.6-kb haplotype within SMAD3 containing numerous single-nucleotide polymorphisms (SNPs) in high LD. SNPs rs17293632 and rs4562997 were identified as functional variants of SMAD3 by luciferase assays within the LD region. These variants regulate SMAD3 transcription in an allele-specific manner through enhancer elements in introns of SMAD3. Knockdown of SMAD3 in thyroid cancer cell lines revealed its regulatory gene network including two upregulated genes, SPRY4 and SPRY4-IT1. Sequence analysis and ChIP assays validated the actual binding of SMAD3 protein to multiple SMAD binding element sites in the region upstream of SPRY4. CONCLUSION: Our data provide a functional annotation of the 15q22 thyroid cancer risk locus.


Assuntos
Proteína Smad3/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 15 , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Ligação Proteica , Proteína Smad3/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo
19.
J Clin Endocrinol Metab ; 103(4): 1369-1379, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29121253

RESUMO

Context: Previous genome-wide association studies have shown that single-nucleotide polymorphism (SNP) rs2439302 in chromosome 8p12 is significantly associated with papillary thyroid carcinoma (PTC) risk and dysregulated NRG1 expression. The underlying mechanisms remain to be discovered. Objective: To evaluate the expression of NRG1 isoforms, candidate functional variants, and potential genes downstream of NRG1 in thyroid tissue. Methods: Quantitative reverse transcription polymerase chain reaction was applied for gene expression analysis. SNaPshot assay, haplotype, and computer analyses were performed to evaluate candidate functional variants. Other functional assays [chromatin immunoprecipitation (ChIP) assay, luciferase assay, small interfering RNA knockdown, and RNA sequencing] were performed. Results: Three NRG1 isoforms (NM_004495, NM_013958, and NM_001160008) tested were highly expressed in thyroid tissue. The expression levels of the three isoforms were significantly correlated with the genotypes of rs2439302. A DNA block of ~32 kb containing the risk G allele of rs2439302 was revealed, harboring multiple candidate functional variants. ChIP assay for active chromatin markers indicated at least nine regions in the DNA block showing strong H3Kme1 and H3K27Ac signals in thyroid tissue. Luciferase reporter assays revealed differential allelic activities associated with seven SNPs. Knocking down NRG1 in primary thyroid cells revealed downstream or interacting genes related to NRG1. Conclusions: Our data suggest a role for transcriptional regulation of NRG1 in the predisposition to PTC.


Assuntos
Carcinoma Papilar/genética , Neuregulina-1/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Carcinoma Papilar/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neuregulina-1/biossíntese , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Locos de Características Quantitativas , RNA Interferente Pequeno/genética , Câncer Papilífero da Tireoide , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Transcrição Genética
20.
Ann Surg Oncol ; 25(2): 520-527, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29164414

RESUMO

BACKGROUND: The 7th AJCC T-stage system for adrenocortical carcinoma (ACC), based on size and extra-adrenal invasion, does not adequately stratify patients by survival. Lymphovascular invasion (LVI) is a known poor prognostic factor. We propose a novel T-stage system that incorporates LVI to better risk-stratify patients undergoing resection for ACC. METHOD: Patients undergoing curative-intent resections for ACC from 1993 to 2014 at 13 institutions comprising the US ACC Group were included. Primary outcome was disease-specific survival (DSS). RESULTS: Of the 265 patients with ACC, 149 were included for analysis. The current T-stage system failed to differentiate patients with T2 versus T3 disease (p = 0.10). Presence of LVI was associated with worse DSS versus no LVI (36 mo vs. 168 mo; p = 0.001). After accounting for the individual components of the current T-stage system (size, extra-adrenal invasion), LVI remained a poor prognostic factor on multivariable analysis (hazard ratio 2.14, 95% confidence interval 1.05-4.38, p = 0.04). LVI positivity further stratified patients with T2 and T3 disease (T2: 37 mo vs. median not reached; T3: 36 mo vs. 96 mo; p = 0.03) but did not influence survival in patients with T1 or T4 disease. By incorporating LVI, a new T-stage classification system was created: [T1: ≤ 5 cm, (-)local invasion, (+/-)LVI; T2: > 5 cm, (-)local invasion, (-)LVI OR any size, (+)local invasion, (-)LVI; T3: > 5 cm, (-)local invasion, (+)LVI OR any size, (+)local invasion, (+)LVI; T4: any size, (+)adjacent organ invasion, (+/-)LVI]. Each progressive new T-stage group was associated with worse median DSS (T1: 167 mo; T2: 96 mo; T3: 37 mo; T4: 15 mo; p < 0.001). CONCLUSIONS: Compared with the current T-stage system, the proposed T-stage system, which incorporates LVI, better differentiates T2 and T3 disease and accurately stratifies patients by disease-specific survival. If externally validated, this T-stage classification should be considered for future AJCC staging systems.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Adrenalectomia/mortalidade , Carcinoma Adrenocortical/secundário , Neoplasias do Córtex Suprarrenal/classificação , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/classificação , Carcinoma Adrenocortical/cirurgia , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Carga Tumoral , Estados Unidos
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