RESUMO
OBJECTIVE(S): Identifying provider variation in surgical costs could control rising healthcare expenditure and deliver cost-effective care. While these efforts have mostly focused on complex and expensive operations, provider-level variation in costs of thyroidectomy has not been well examined. METHODS: We retrospectively evaluated 921 consecutive total thyroidectomies performed by 14 surgeons at our institution between September 2011 and July 2016. Data were extracted from the Change Healthcare Performance Analytics Program. RESULTS: Mean patient age was 47.4 ± 0.5 y, 81% were females, 64.7% were Caucasians, and 18.8% were outpatients. The number of thyroidectomies performed by the 14 surgeons ranged from 4 to 597 (mean = 66). The mean costs per provider varied widely from $4,293 to $15,529 (P < 0.001). The mean length of stay was 1d ± .03 with wide variation among providers (0-6 d). Providers whose hospital cost exceeded the institutional mean demonstrated significantly higher anesthesia fees and lab costs (P < 0.001). CONCLUSIONS: We found substantial variation in hospital cost among providers for thyroidectomy despite practicing in the same academic institution, with some surgeons spending 3x more for the same operation. Implementing institutional standards of practice could reduce variation and the costs of surgical care.
Assuntos
Tireoidectomia , Honorários e Preços , Feminino , Gastos em Saúde , Custos Hospitalares , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Cirurgiões/economia , Tireoidectomia/economiaRESUMO
Few models exist for studying neuroendocrine tumors (NETs), and there are mounting concerns that the currently available array of cell lines is not representative of NET biology. The lack of stable patient-derived NET xenograft models further limits the scientific community's ability to make conclusions about NETs and their response to therapy in patients. To address these limitations, we propose the use of an ex vivo 3D flow-perfusion bioreactor system for culturing and studying patient-derived NET surrogates. Herein, we demonstrate the utility of the bioreactor system for culturing NET surrogates and provide methods for evaluating the efficacy of therapeutic agents on human NET cell line xenograft constructs and patient-derived NET surrogates. We also demonstrate that patient-derived NET tissues can be propagated using the bioreactor system and investigate the near-infrared (NIR) dye IR-783 for its use in monitoring their status within the bioreactor. The results indicate that the bioreactor system and similar 3D culture models may be valuable tools for culturing patient-derived NETs and monitoring their response to therapy ex vivo.
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Reatores Biológicos/estatística & dados numéricos , Técnicas de Cultura de Células/métodos , Neoplasias Intestinais/patologia , Neoplasias Pulmonares/patologia , Modelos Biológicos , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/patologia , Neoplasias da Glândula Tireoide/patologia , Animais , Humanos , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In an effort to discover viable systemic chemotherapeutic agents for neuroendocrine tumors (NETs), we screened a small library of 18 drug-like compounds obtained from the Velu lab against pulmonary (H727) and thyroid (MZ-CRC-1 and TT) neuroendocrine tumor-derived cell lines. Two potent lead compounds (DHN-II-84 and DHN-III-14) identified from this screening were found to be analogs of the natural product makaluvamine. We further characterized the antitumor activities of these two compounds using pulmonary (H727), thyroid (MZ-CRC-1) and pancreatic (BON) neuroendocrine tumor cell lines. Flow cytometry showed a dose-dependent increase in apoptosis in all cell lines. Induction of apoptosis with these compounds was also supported by the decrease in myeloid cell leukemia-1 (MCL-1) and X-chromosome linked inhibitor of apoptosis (XIAP) detected by Western blot. Compound treatment decreased NET markers chromogranin A (CgA) and achaete-scute homolog 1 (ASCL1) in a dose-dependent manner. Moreover, the gene expression analysis showed that the compound treatment reduced c-Kit proto-oncogene expression in the NET cell lines. Induction of apoptosis could also have been caused by the inhibition of c-Kit expression, in addition to the known mechanisms such as damage of DNA by topoisomerase II inhibition for this class of compounds. In summary, makaluvamine analogs DHN-II-84 and DHN-III-14 induced apoptosis, decreased neuroendocrine tumor markers, and showed promising antitumor activity in pulmonary, thyroid, and pancreatic NET cell lines, and hold potential to be developed as an effective treatment to combat neuroendocrine tumors.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Tumores Neuroendócrinos/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Pirróis/química , Pirróis/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Proto-Oncogene MasRESUMO
We describe a neonate with an unusual vascular ring formed by a right-sided aortic arch with associated coarctation and distal hypoplasia in the presence of an aberrant left subclavian artery. The descending aorta traveled behind the esophagus to descend on the left side of the spine. A left ductus arteriosus connected to the descending aorta completing the vascular ring, with notable esophageal compression. Surgical correction was accomplished through median sternotomy, resection of the hypoplastic circumflex arch, aortic arch advancement, and end-to-side anastomosis.
Assuntos
Aorta Torácica/cirurgia , Coartação Aórtica/cirurgia , Anormalidades Cardiovasculares/cirurgia , Artéria Subclávia/anormalidades , Anel Vascular/cirurgia , Anastomose Cirúrgica , Canal Arterial/cirurgia , Permeabilidade do Canal Arterial/cirurgia , Ecocardiografia , Comunicação Interventricular/cirurgia , Humanos , Recém-Nascido , Esternotomia , Artéria Subclávia/cirurgiaRESUMO
BACKGROUND: The internet is a valuable resource for residency and fellowship applicants when deciding where to apply or interview, yet program websites have shown critical deficiencies in accessibility and content. No analysis of cardiothoracic surgery program websites has been performed. METHODS: Online databases and Google were used to identify integrated, 4 + 3, and traditional cardiothoracic surgery residency and fellowship programs. The accessibility of websites from each of these sources was assessed and the presence or absence of content that may be relevant to applicants was evaluated by two reviewers. RESULTS: Eighty-nine active programs were identified and 86 had functional websites. Website content and accessibility were overall suboptimal in all 86 of these programs. Google was the most reliable means of accessing a program's website. Fifty percent of integrated program websites and 60% of traditional fellowship websites contained less than half of the content assessed. Information on 4 + 3 programs was extremely limited. CONCLUSIONS: Despite the value that a program's website could provide to applicants when making decisions during the application process, cardiothoracic surgery residency and fellowship websites remain difficult to access and are not uniformly providing information that may be important. Improving cardiothoracic website accessibility and content may have implications for attracting the most competitive applicants while limiting the financial and scheduling demands associated with the interview process. Creation of a current database containing standardized information relevant to applicants may improve applicants' ability to form an impression of a program before scheduling an interview.
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Bolsas de Estudo/organização & administração , Internet , Internato e Residência/organização & administração , Candidatura a Emprego , Cirurgia Torácica/educação , Procedimentos Cirúrgicos Cardíacos/educação , Humanos , Estados UnidosRESUMO
The Notch family is a highly conserved gene group that regulates cell-cell interaction, embryogenesis, and tissue commitment. This review article focuses on the third Notch family subtype, Notch3. Regulation via Notch3 signaling was first implicated in vasculogenesis. However, more recent findings suggest that Notch3 signaling may play an important role in oncogenesis, tumor maintenance, and resistance to chemotherapy. Its role is mainly oncogenic, although in some cancers it appears to be tumor suppressive. Despite the wealth of published literature, it remains relatively underexplored and requires further research to shed more light on its role in cancer development, determine its tissue-specific function, and elaborate novel treatment strategies. Herein we summarize the role of Notch3 in cancer, possible mechanisms of its action, and current cancer treatment strategies targeting Notch3 signaling. IMPLICATIONS FOR PRACTICE: The Notch family is a highly conserved gene group that regulates cell-cell interaction, embryogenesis, and tissue commitment. This review summarizes the existing data on the third subtype of the Notch family, Notch3. The role of Notch3 in different types of cancers is discussed, as well as implications of its modification and new strategies to affect Notch3 signaling activity.
Assuntos
Neoplasias/genética , Neoplasias/metabolismo , Receptor Notch3/genética , Receptor Notch3/metabolismo , Animais , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: Identifying hospital and provider variation in surgical cost is a potent method for controlling rising healthcare expenditure and delivering cost-effective care. The purpose of this study was to examine the variation of hospital cost by providers for parathyroidectomy in a single academic institution. METHODS: We retrospectively evaluated 894 consecutive parathyroidectomies under 8 surgeons in our institution between September 2011 and July 2016. Total duration of stay and cost were evaluated using nonparametric tests. Categorical variables were evaluated with χ2. RESULTS: The median total hospital cost for parathyroidectomy was $4,863.28 (interquartile range: 4,196-5,764), but the median costs per provider varied widely from $4,522.30 to $12,072.87. The median duration of stay was 0 days (IQR: 0-1) and demonstrated a wide variation among providers. Longer duration of practice was associated with lower cost. Despite the variation, only 2% was readmitted after discharge with no patient mortality. CONCLUSION: We found substantial variation in hospital cost among providers for parathyroidectomy despite practicing in the same academic institution, with some surgeons spending 4 time more for the same operation. Implementing institutional standards of practice could be a method to decrease variation and costs of surgical care.
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Custos Hospitalares , Doenças das Paratireoides/cirurgia , Paratireoidectomia/economia , Adulto , Idoso , Feminino , Humanos , Tempo de Internação/economia , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica/economia , Estudos RetrospectivosRESUMO
Novel therapies for neuroendocrine (NE) cancers are desperately needed as they frequently present as metastatic disease and cause debilitating symptoms by secreting excessive hormones. Induction of Notch isoforms has a tumor suppressive effect in NE cancer cell lines, and we have observed that histone deacetylase inhibitors (HDACi) potently activate Notch. In this study, we describe the potential for Burkholderia thailandensis-derived class I HDACi thailandepsin A (TDP-A) as a Notch activator and therapeutic agent against NE cancer. IC50 for TDP-A was determined to be 4-6 nM in NE cancer cell lines (BON, MZ-CRC-1, and TT) without cytotoxicity to lung fibroblasts. The binding characteristics of TDP-A to its target HDAC1 was examined using bioluminescence resonance energy transfer (BRET). Western blot and flow cytometry analysis showed that TDP-A induces cell cycle arrest and apoptosis in a dose-dependent manner. TDP-A dose-dependently activated the Notch pathway as measured by increasing functional CBF1-luciferase reporter signal and mRNA and protein expressions of Notch isoforms, which were attenuated by pretreatment with γ-secretase inhibitor DAPT. Furthermore, TDP-A lead to changes in expression level of downstream targets of Notch pathway and reduced expression of NE cancer markers. An in vivo study demonstrated that TDP-A suppressed NE cancer progression. These results show that TDP-A, as a Notch activator, is a promising agent against NE cancers.
RESUMO
BACKGROUND: Recent studies suggest that the encapsulated form of follicular variant of papillary thyroid cancer (eFVPTC) behaves more similarly to benign lesions and can be treated with thyroid lobectomy alone instead of total thyroidectomy. To distinguish aggressive cancers from more benign lesions more clearly, the objective of this study was to determine if the eFVPTC behaves less aggressively than the nonencapsulated variant (neFVPTC). METHODS: A prospectively collected endocrine surgery database in our institution was reviewed for all patients with FVPTC on surgical pathology from 1999 to 2012. Samples were rereviewed to determine if the tumor was eFVPTC or neFVPTC, which were correlated with patient outcomes. RESULTS: Of the 68 patients, 59 (87%) had eFVPTC and 9 (13%) had neFVPTC. The mean age was 48 y and 63% were female. Fifty-four of 64 patients (84%) who had a total thyroidectomy received radioactive iodine. The eFVPTC group had lower rates of cervical LN involvement (5% versus 22%, P = 0.2504). The median follow-up time was 3 y (0-13 y) and only two patients had recurrence, one with eFVPTC and one with neFVPTC. None of the patients had distant metastasis or died of their disease. CONCLUSIONS: eFVPTCs appear to have a lower rate of cervical lymph node metastases compared with neFVPTCs, but recurrent disease may be seen in both subtypes. These findings suggest eFVPTC can be managed more conservatively.
Assuntos
Carcinoma/patologia , Neoplasias da Glândula Tireoide/patologia , Adulto , Idoso , Carcinoma/cirurgia , Carcinoma Papilar , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estudos Retrospectivos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Resultado do TratamentoRESUMO
BACKGROUND: Thyroid tumorigenesis is characterized by a progressive loss of differentiation exhibited by a range of disease variants. The Notch receptor family (1-4) regulates developmental progression in both normal and cancerous tissues. This study sought to characterize the third Notch isoform (Notch3) across the various differentiated states of thyroid cancer, and determine its clinical impact. METHODS: Notch3 expression was analyzed in a tissue microarray of normal and pathologic thyroid biopsies from 155 patients. The functional role of Notch3 was then investigated by upregulating its expression in a follicular thyroid cancer (FTC) cell line. RESULTS: Notch3 expression regressed across decreasingly differentiated, increasingly malignant thyroid specimens, correlated with clinicopathological attributes reflecting poor prognosis, and independently predicted survival following univariate and multivariate analyses. Overexpression of the active Notch3 intracellular domain (NICD3) in a gain-of-function FTC line led to functional activation of centromere-binding protein 1, while increasing thyroid-specific gene transcription. NICD3 induction also reduced tumor burden in vivo and initiated the intrinsic apoptotic cascade, alongside suppressing cyclin and B-cell lymphoma 2 family expression. CONCLUSIONS: Loss of Notch3 expression may be fundamental to the process of dedifferentiation that accompanies thyroid oncogenesis. Conversely, activation of Notch3 in thyroid cancer exerts an antiproliferative effect and restores elements of a differentiated phenotype. These findings provide preclinical rationale for evaluating Notch3 as a disease prognosticator and therapeutic target in advanced thyroid cancer. Cancer 2017;123:769-82. © 2016 American Cancer Society.
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Carcinogênese/genética , Prognóstico , Receptor Notch3/biossíntese , Neoplasias da Glândula Tireoide/genética , Animais , Apoptose/genética , Biópsia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Receptor Notch3/genética , Transdução de Sinais , Neoplasias da Glândula Tireoide/classificação , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Notch1, a transmembrane receptor, has been recently shown to aid in the determination of thyroid cell fate associated with tumorigenesis. This study aimed to investigate the clinical relevance of Notch1 and its role in the regulation of differentiated thyroid cancer (DTC) behavior. EXPERIMENTAL DESIGN: We examined Notch1 expression level and its relationship with clinicopathologic features and outcomes of DTC. Notch1 intracellular domain (NICD) was further characterized both in vitro and in vivo by gain-of-function assays using an inducible system. RESULTS: Notch1 expression levels were downregulated in primary DTC tissue samples compared with contralateral nontumor and benign thyroid tissues. Decreased Notch1 expression in DTC was associated with advanced patient age (P = 0.032) and the presence of extrathyroidal invasion (P = 0.005). Patients with lower Notch1 expression had a significantly higher recurrence rate (P = 0.038). Restoration of NICD in a stably doxycycline-inducible metastatic DTC cell line reduced cell growth and migration profoundly. Using an orthotopic thyroid cancer model, NICD induction significantly reduced the growth of the primary thyroid tumor and inhibited the development of lung metastasis. Serpin peptidase inhibitor, clade E, member 1 (SERPINE1) was discovered by microarray as the most significant gene downregulated by NICD. Further validation showed that the induction of NICD reduced SERPINE1 expression in a dose-dependent manner, whereas restoration of a relative higher level of SERPINE1 was observed with NICD back to minimal level. In addition, SERPINE1 knock-down inhibited DTC cell migration. CONCLUSIONS: Notch1 regulates the aggressive phenotypes of DTC, which could be mediated by SERPINE1 inhibition. Notch1/SERPINE1 axis warrants further investigation as a novel therapeutic target for advanced DTC. Clin Cancer Res; 22(14); 3582-92. ©2016 AACR.