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BACKGROUND: Adrenal cysts are rare and appropriate management is unclear due to a lack of data on their natural history. Understanding adrenal cyst growth patterns would assist in clinical management. METHODS: This single-institution study included all adult patients diagnosed with simple adrenal cysts between 2004 and 2021. Baseline characteristics and outcomes of those who underwent resection (ADX) or observation (OBS) were compared using the chi-squared test, student's t-test, and Wilcoxon rank-sum test. Growth curves and sensitivity analysis were plotted for all patients who had follow-up imaging. RESULTS: We identified 77 patients with imaging-confirmed adrenal cysts. The majority were female (75.3%) and more than half were white (55.8%). One-third of patients underwent ADX, and the remaining were observed. ADX patients were younger (median age [IQR]: 55.5 y [45.0-68.2 y] vs. 44.2 y [38.7-55.0 y], p = 0.01) and more likely to be Hispanic (12% vs. 0%, p = 0.05). ADX patients presented with larger cysts (5.6 vs. 2.6 cm, p = 0.002). The median time from diagnosis to last follow-up was 1.1 y for ADX and 4.1 y for OBS. Average growth for OBS was 0.3 cm/y, while average growth for ADX was 3.9 cm/y. In ADX patients, cysts >10 cm grew significantly faster than cysts <10 cm (median growth rate 13.2 cm/y vs. 0.3 cm/y, p < 0.05). There was no adrenal malignancy diagnosis, hyperfunctionality, or observation-related complications (e.g., rupture). CONCLUSION: While size >4-6 cm has guided surgical referral for solid adrenal masses, this study demonstrates a size threshold of 10 cm, below which asymptomatic, simple adrenal cysts can safely be observed.
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Enfermedades de las Glándulas Suprarrenales , Quistes , Humanos , Femenino , Masculino , Persona de Mediana Edad , Quistes/cirugía , Quistes/diagnóstico por imagen , Quistes/patología , Enfermedades de las Glándulas Suprarrenales/cirugía , Enfermedades de las Glándulas Suprarrenales/diagnóstico por imagen , Enfermedades de las Glándulas Suprarrenales/patología , Enfermedades de las Glándulas Suprarrenales/diagnóstico , Adulto , Anciano , Estudios Retrospectivos , Adrenalectomía/métodos , Espera Vigilante , Tomografía Computarizada por Rayos XRESUMEN
Differentiated thyroid carcinomas is associated with an excellent prognosis. The treatment of choice for differentiated thyroid carcinoma is surgery, followed by radioactive iodine ablation (iodine-131) in select patients and thyroxine therapy in most patients. Surgery is also the main treatment for medullary thyroid carcinoma, and kinase inhibitors may be appropriate for select patients with recurrent or persistent disease that is not resectable. Anaplastic thyroid carcinoma is almost uniformly lethal, and iodine-131 imaging and radioactive iodine cannot be used. When systemic therapy is indicated, targeted therapy options are preferred. This article describes NCCN recommendations regarding management of medullary thyroid carcinoma and anaplastic thyroid carcinoma, and surgical management of differentiated thyroid carcinoma (papillary, follicular, Hürthle cell carcinoma).
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Adenocarcinoma , Yodo , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Adenocarcinoma/tratamiento farmacológico , Carcinoma Neuroendocrino , Humanos , Yodo/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapiaRESUMEN
Permitted daily exposure (PDE) values are used by some toxicologists to support the safety qualification of various types of impurities found in a drug substance (DS) or drug product (DP). Permitted daily exposure values are important tools for the toxicologist, but one must be aware of their limitations to ensure that they are used appropriately and effectively in the risk assessment process. First, a toxicologist must always perform a comprehensive analysis of all available animal and human safety data for an impurity, including identifying any data gaps that may exist. Second, if adequate data are available and there are no genotoxicity concerns, an appropriate well-designed repeat-dose toxicity study in animals should be chosen to calculate the PDE. It is important to note that PDE values qualify general systemic toxicity and not necessarily local toleration end points such as irritation and sensitization that are more concentration than dose dependent. In addition, a PDE value calculated from a general toxicity study in animals may not necessarily qualify for reproductive toxicology end points. Lastly, PDE values should never be thought of as analytical limits for or acceptable levels of an impurity in a DS or DP, as this ignores quality considerations. Using safety information from several chemicals as proxy impurities, this article serves as an educational primer to facilitate a better understanding of the development and use of PDE values in the risk assessment process.
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Exposición a Riesgos Ambientales/normas , Contaminantes Ambientales/toxicidad , Nivel sin Efectos Adversos Observados , Animales , Humanos , Medición de RiesgoRESUMEN
BACKGROUND: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. We queried whether comprehensive genomic profiling (CGP) of PC might identify genomic alterations (GAs), which would suggest benefit from rationally matched therapeutics. METHODS: We performed hybrid-capture-based CGP to identify GAs and tumor mutational burden (TMB) in tumors from patients with this malignancy. RESULTS: There were 85 total GAs in 16 cases (5.3 GAs per case), and the median TMB was 1.7 mutations per megabase (m/Mb), with three cases having >20 m/Mb (18.7%). The genes most frequently harboring GA were CDC73 (38%), TP53 (38%), and MEN1 (31%). All MEN1-mutated cases also had loss of heterozygosity at that locus, but in contrast all CDC73-mutated cases retained heterozygosity. GAs suggesting potential benefit from matched targeted therapy were identified in 11 patients (69%) and most frequently found in PTEN (25%), NF1 (12.5%), KDR (12.5%), PIK3CA (12.5%), and TSC2 (12.5%). A patient whose tumor harbored KDR T668 K and who was treated with cabozantinib experienced a > 50% drop in parathyroid hormone level and radiographic partial response of 5.4 months with duration limited by toxicity. CONCLUSION: CGP identified GAs in PC that suggest benefit from targeted therapy, as supported by an index case of response to a matched tyrosine kinase inhibitor. Moreover, the unexpectedly high frequency of high TMB (>20 m/Mb) suggests a subset of PC may benefit from immune checkpoint inhibitors. IMPLICATIONS FOR PRACTICE: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. However, its molecular characteristics remain unclear, with few systemic therapeutic options available for this tumor. Hybrid-capture-based comprehensive genomic profiling of 16 primary cancers demonstrated presence of potentially actionable genomic alterations, including PTEN, NF1, KDR, PIK3CA, and TSC2, and a subset of hypermutated cancers with more than 20 mutations per megabase, the latter of which could benefit from immune checkpoint inhibitor therapy. A case benefiting from rationally matched targeted therapy for activating KDR mutation is also presented. These findings should be further investigated for their therapeutic potential.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Neoplasias de las Paratiroides/tratamiento farmacológico , Medicina de Precisión/métodos , Adulto , Anciano , Antineoplásicos/farmacología , Biomarcadores de Tumor/antagonistas & inhibidores , Estudios de Cohortes , Femenino , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Tasa de Mutación , Neoplasias de las Paratiroides/genética , Selección de PacienteRESUMEN
Tofacitinib, an oral Janus kinase (JAK) inhibitor for treatment of rheumatoid arthritis, targets JAK1, JAK3, and to a lesser extent JAK2 and TYK2. JAK1/3 inhibition impairs gamma common chain cytokine receptor signaling, important in lymphocyte development, homeostasis and function. Adult and juvenile cynomolgus monkey and rat studies were conducted and the impact of tofacitinib on immune parameters (lymphoid tissues and lymphocyte subsets) and function (T-dependent antibody response (TDAR), mitogen-induced T cell proliferation) assessed. Tofacitinib administration decreased circulating T cells and NK cells in juvenile and adult animals of both species. B cell decreases were observed only in rats. These changes and decreased lymphoid tissue cellularity are consistent with the expected pharmacology of tofacitinib. No differences were observed between juvenile and adult animals, either in terms of doses at which effects were observed or differential effects on immune endpoints. Lymphomas were observed in three adult monkeys. Tofacitinib impaired the primary TDAR in juvenile monkeys, although a recall response was generated. Complete or partial reversal of the effects on the immune system was observed.
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Envejecimiento/inmunología , Inhibidores de las Cinasas Janus/toxicidad , Piperidinas/toxicidad , Pirimidinas/toxicidad , Pirroles/toxicidad , Administración Oral , Animales , Antígenos/inmunología , Recuento de Eritrocitos , Femenino , Hematócrito , Hemocianinas/inmunología , Hemoglobinas/análisis , Inhibidores de las Cinasas Janus/farmacocinética , Recuento de Leucocitos , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Linfoma de Células B/inducido químicamente , Macaca fascicularis , Masculino , Tamaño de los Órganos/efectos de los fármacos , Piperidinas/farmacocinética , Pirimidinas/farmacocinética , Pirroles/farmacocinética , Ratas Sprague-Dawley , Bazo/efectos de los fármacos , Bazo/patología , Timo/efectos de los fármacos , Timo/patología , Pruebas de Toxicidad CrónicaRESUMEN
Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis. In the 2-year carcinogenicity study with tofacitinib, increased incidence of hibernoma (a neoplasm of brown adipose tissue [BAT]) was noted in female rats at ≥30 mg/kg/day (≥41x human exposure multiples). Thus, signaling pathways within BAT were investigated by measuring BAT: weight, cell proliferation biomarkers, content of basal and prolactin-induced phosphorylated Signal Transducer and Activator of Transcription (STAT), and uncoupling protein 1 (UCP-1). The relationship between cardiovascular hemodynamics and plasma norepinephrine (NE) levels was also investigated. Tofacitinib administered to female rats at doses of 10, 30, or 75 mg/kg/day for 14 days increased BAT weight at 75 mg/kg/day and cell proliferation at ≥30 mg/kg/day. JAK inhibition, observed as lower pSTAT3 and pSTAT5 in BAT, was noted at ≥10 mg/kg/day, while lower activity of BAT was observed as lower UCP-1 protein at ≥30 mg/kg/day. In cultured brown adipocytes, prolactin-induced increase in pSTAT5 and pSTAT3 were inhibited by tofacitinib in a concentration-dependent manner. Tofacitinib lowered blood pressure, increased heart rate, and resulted in dose-dependent increases in circulating NE. Thus, JAK/STAT inhibition in BAT and sympathetic stimulation are two factors which might contribute to the genesis of hibernomas by tofacitinib in rats.
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Lipoma/inducido químicamente , Piperidinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Pirroles/efectos adversos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Inhibidores de las Cinasas Janus/efectos adversos , Inhibidores de las Cinasas Janus/farmacología , Lipoma/metabolismo , Masculino , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Factores de Transcripción STAT/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transactivadores/efectos adversos , Transactivadores/farmacologíaRESUMEN
Leachables from pharmaceutical container closure systems can present potential safety risks to patients. Extractables studies may be performed as a risk mitigation activity to identify potential leachables for dosage forms with a high degree of concern associated with the route of administration. To address safety concerns, approaches to toxicological safety evaluation of extractables and leachables have been developed and applied by pharmaceutical and biologics manufacturers. Details of these approaches may differ depending on the nature of the final drug product. These may include application, the formulation, route of administration and length of use. Current regulatory guidelines and industry standards provide general guidance on compound specific safety assessments but do not provide a comprehensive approach to safety evaluations of leachables and/or extractables. This paper provides a perspective on approaches to safety evaluations by reviewing and applying general concepts and integrating key steps in the toxicological evaluation of individual extractables or leachables. These include application of structure activity relationship studies, development of permitted daily exposure (PDE) values, and use of safety threshold concepts. Case studies are provided. The concepts presented seek to encourage discussion in the scientific community, and are not intended to represent a final opinion or "guidelines."
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Productos Biológicos/efectos adversos , Productos Biológicos/química , Liberación de Fármacos , Preparaciones Farmacéuticas/química , Seguridad , Productos Biológicos/administración & dosificación , Seguridad Química , HumanosRESUMEN
BACKGROUND: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor α (PDGFRα), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC). METHODS: Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death. Previous VEGFR-targeted therapy was permitted. The primary endpoint was the objective response rate (ORR) based on independent imaging review. Secondary endpoints included progression-free survival (PFS) and safety. Serum levels of 51 circulating cytokines and angiogenic factors also were assessed. RESULTS: After ≥14 months of follow-up, patients had an ORR of 50% (95% confidence interval [CI], 37%-63%) with only partial responses reported. The median time to response was 3.6 months, the median response duration was 12.7 months, and the median PFS was 12.6 months (95% CI, 9.9-16.1 months). The ORR for patients who had received previous VEGF therapy (n = 17) was 59% (95% CI, 33%-82%). Lower baseline levels of angiopoietin-2 were suggestive of tumor response and longer PFS. Grade 3 and 4 treatment-emergent adverse events, regardless of their relation to treatment, occurred in 72% of patients and most frequently included weight loss (12%), hypertension (10%), proteinuria (10%), and diarrhea (10%). CONCLUSIONS: In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Cancer 2015;121:2749-2756. © 2015 American Cancer Society.
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Antineoplásicos/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Adulto , Anciano , Biomarcadores de Tumor/análisis , Progresión de la Enfermedad , Femenino , Humanos , Radioisótopos de Yodo/efectos adversos , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Proto-Oncogenes Mas , Quinolinas/efectos adversos , Neoplasias de la Tiroides/mortalidad , Resultado del TratamientoRESUMEN
This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.
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Carcinoma Anaplásico de Tiroides/diagnóstico , Carcinoma Anaplásico de Tiroides/terapia , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Docetaxel , Doxorrubicina/administración & dosificación , Humanos , Paclitaxel/administración & dosificación , Radioterapia de Intensidad Modulada , Taxoides/administración & dosificación , Carcinoma Anaplásico de Tiroides/secundario , Neoplasias de la Tiroides/patología , TiroidectomíaRESUMEN
These NCCN Guidelines Insights focus on some of the major updates to the 2014 NCCN Guidelines for Thyroid Carcinoma. Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with radioactive iodine. Sorafenib may be considered for select patients with metastatic differentiated thyroid carcinoma, whereas vandetanib or cabozantinib may be recommended for select patients with metastatic medullary thyroid carcinoma. Other kinase inhibitors may be considered for select patients with either type of thyroid carcinoma. A new section on "Principles of Kinase Inhibitor Therapy in Advanced Thyroid Cancer" was added to the NCCN Guidelines to assist with using these novel targeted agents.
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Adenocarcinoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Adenocarcinoma/patología , Anilidas/uso terapéutico , Carcinoma Neuroendocrino , Guías como Asunto , Humanos , Metástasis de la Neoplasia , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéutico , Sorafenib , Neoplasias de la Tiroides/patologíaRESUMEN
Metastatic lung neuroendocrine carcinomas provide diagnostic challenges in identifying the cell of origin. High level calcitonin expression is not pathognomonic for medullary thyroid cancer. Tumor mutation analysis may provide essential clues regarding tissue origin and treatment targets. Oncogenic RET gene fusions have been identified in non-small cell lung cancer and non-medullary thyroid cancers, whereas RET point mutations are the key genetic finding in both inherited and sporadic MTC. Patients who receive radiation for the treatment of other cancers have an increased risk of developing a second malignancy, including a neuroendocrine carcinoma. Herein, we present a case of calcitonin-rich neuroendocrine carcinoma emerging on a background of prior radiation and chemotherapy for the treatment of Hodgkin's disease. Identification of a RET gene rearrangement (KIF5B-RET) led to initial successful treatment with selpercatinib, with eventual resistance associated with an activating mutation involving the MEK1 protein (MAP2K1 p. E102-I103 del) that led to relapse and progression of the disease.
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Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.
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Adenocarcinoma , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Mutación/genética , GenómicaRESUMEN
OBJECTIVES: Pheochromocytomas are increasingly being discovered incidentally on imaging studies performed without clinical suspicion of the existence of an adrenal lesion. We aimed to determine the rate of diagnosis of adrenal pheochromocytoma as an incidental finding during a recent 7-year period. METHODS: We obtained the Department of Pathology database to study all the patients at our institution with newly diagnosed pheochromocytomas in the 7-year period from 2005 to 2011 to determine the clinical presentation and the means of diagnosis. RESULTS: In 40 (70.2%) of the 57 patients, an adrenal pheochromocytoma was detected in an imaging study performed without suspicion of an adrenal lesion. There were 13 chest computed tomography studies-8 to evaluate for possible pulmonary emboli. Other indications included abdominal pain or discomfort (n = 8), trauma (n = 3), abnormal liver function tests (n = 3), suspect renal artery stenosis (n = 3), hematuria (n = 2), colitis (n = 2), and 4 miscellaneous indications. DISCUSSION: Our study documents that the commonest current means of initial detection of pheochromocytoma is by serendipitous discovery. In 16 of our 40 patients with serendipitously discovered pheochromocytomas, there were no clinical symptoms of pheochromocytoma; these were true incidentalomas. More than two thirds of the new cases of pheochromocytoma were detected by serendipity (found during studies not performed to evaluate for pheochromocytoma), approximately one third were true incidentalomas (pheochromocytomas in patients without symptoms). CONCLUSIONS: In a 7-year period at a single institution, 40 patients, 70% of new cases of surgically proven pheochromocytoma, were initially detected by serendipity. Sixteen patients, 40% of those incidentally discovered represented true examples of "incidentalomas."
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Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/epidemiología , Hallazgos Incidentales , Feocromocitoma/diagnóstico por imagen , Feocromocitoma/epidemiología , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Adulto , Anciano , Femenino , Humanos , Incidencia , Masculino , Maryland/epidemiología , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Notch signaling regulates cell fate decisions in a wide variety of adult and embryonic tissues. Here we show that Notch pathway components and Notch target genes are upregulated in invasive pancreatic cancer, as well as in pancreatic cancer precursors from both mouse and human. In mouse pancreas, ectopic Notch activation results in accumulation of nestin-positive precursor cells and expansion of metaplastic ductal epithelium, previously identified as a precursor lesion for pancreatic cancer. Notch is also activated as a direct consequence of EGF receptor activation in exocrine pancreas and is required for TGF alpha-induced changes in epithelial differentiation. These findings suggest that Notch mediates the tumor-initiating effects of TG alpha by expanding a population of undifferentiated precursor cells.
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Diferenciación Celular/efectos de los fármacos , Células Epiteliales/patología , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso , Neoplasias Pancreáticas/metabolismo , Factor de Crecimiento Transformador alfa/farmacología , Animales , Biomarcadores/análisis , Carcinoma Ductal/metabolismo , Células Cultivadas , Progresión de la Enfermedad , Receptores ErbB/metabolismo , Perfilación de la Expresión Génica , Humanos , Ratones , Ratones Transgénicos , Invasividad Neoplásica , Nestina , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Pancreáticas/patología , Receptores Notch , Transducción de Señal , Regulación hacia ArribaRESUMEN
Tyrosine kinase inhibitors play an important role in the armamentarium against cancer. Lenvatinib is a multiple kinase inhibitor approved by the Food and Drugs Administration (FDA) for the treatment of advanced and radioresistant thyroid carcinomas and, in combination with everolimus, for renal cell carcinoma and unresectable hepatocellular carcinoma. The anti-tumoral activity is largely dependent on inhibition of neo-angiogenesis, and established side effects of anti-angiogenetic therapeutics include renal thrombotic microangiopathy (TMA). Here, we describe three cases of biopsy-proven renal TMA clinically presenting with proteinuria and stable serum creatinine in patients receiving lenvatinib for thyroid cancer. Microangiopathic lesions included glomerular basement membrane reduplication with segmental cellular interposition, mesangiolysis, and focal intracapillary and arteriolar thrombi. Drug-dose reduction or withdrawal was effective in renal function preservation, but cancer progressed in all patients. The management of lenvatinib-induced renal TMA remains a challenge. The best therapy in these patients is still uncertain. Earlier and more precise measurement of urine protein levels, allowing for early dose adjustment, could be effective in preventing further damage and drug discontinuation.
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Carcinoma de Células Renales , Neoplasias Renales , Microangiopatías Trombóticas , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Humanos , Riñón/patología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Compuestos de Fenilurea/efectos adversos , Quinolinas , Microangiopatías Trombóticas/inducido químicamente , Microangiopatías Trombóticas/tratamiento farmacológico , Microangiopatías Trombóticas/patologíaRESUMEN
Oral phosphodiesterase (PDE) 4 inhibitors have demonstrated clinical efficacy in chronic obstructive pulmonary disease and asthma. Preclinical and clinical investigation of inhaled PDE4 inhibitors is ongoing. 6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-methyloxy)phenyl]amino}-3-quinolinecarboxamide (GSK256066) is an exceptionally high-affinity and selective inhibitor of PDE4 designed for inhaled delivery. The aim of these studies was to investigate the potency, duration of action, and therapeutic index of GSK256066 in animal models of pulmonary inflammation. The effects of intratracheally administered GSK256066 were investigated in rat lipopolysaccharide (LPS)- and ovalbumin (OVA)-induced models of acute pulmonary inflammation. In some studies, fluticasone propionate (FP) was included as a comparator. The therapeutic index (anti-inflammatory effect versus emesis) of GSK256066 was studied in ferrets where acute pulmonary inflammation was induced with inhaled LPS. In rats, GSK256066 and FP caused significant (p < 0.05) inhibition of LPS-induced pulmonary neutrophilia. The duration of action of GSK256066 at 10 × ED(50) dose (10 µg/kg) was 12 h. GSK256066 and FP also inhibited LPS-induced increases in exhaled nitric oxide (ED(50) 35 and 92 µg/kg, respectively). In addition, GSK256066 inhibited pulmonary eosinophilia in rats exposed to OVA (ED(50) 0.4 µg/kg). In ferrets, inhaled GSK256066 inhibited LPS-induced pulmonary neutrophilia (ED(50) 18 µg/kg), and no emetic episodes were observed. Thus, GSK256066 may have an improved therapeutic index compared with oral PDE4 inhibitors, e.g., cilomilast and roflumilast. In summary, GSK256066 demonstrates potent and long-lasting anti-inflammatory effects in animal models of pulmonary inflammation and does not induce emetic episodes in ferrets. GSK256066 has potential as an inhaled therapeutic for the treatment of asthma and chronic obstructive pulmonary disease.
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Aminoquinolinas/administración & dosificación , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Sulfonas/administración & dosificación , Administración por Inhalación , Aminoquinolinas/metabolismo , Animales , Eosinofilia/tratamiento farmacológico , Eosinofilia/enzimología , Hurones , Masculino , Inhibidores de Fosfodiesterasa 4/metabolismo , Ratas , Ratas Endogámicas BN , Ratas Sprague-Dawley , Sulfonas/metabolismoRESUMEN
High rates of comorbid chronic pain, anxiety, and mood disorders among individuals with the Ehlers-Danlos syndromes (EDS+) are becoming increasingly recognized, though this complex symptomology remains poorly understood and undertreated. The current project examined whether interoceptive attention regulation is protective against depressive and anxiety symptoms in individuals with suspected EDS+. Data were collected from individuals participating in a transdisciplinary diagnostic visit within an EDS+ specialty consultation clinic. Participants were included in the current analyses (n = 49) if they had complete data on the following measures: the PHQ-8, the GAD-7, the Pain Severity subscale from the West Haven-Yale Multidimensional Pain Inventory, and the Attention Regulation subscale from the Multidimensional Assessment of Interoceptive Awareness. Consistent with expectations, the sample showed high levels of clinically significant anxiety and depressive symptoms. Pain severity ratings were significantly correlated with depressive but not anxiety severity. Moreover, higher levels of perceived interoceptive attention regulation abilities were significantly associated with less severe anxiety and depressive symptoms; however, attention regulation did not moderate the associations of pain with anxiety and depressive symptom severity. CONCLUSIONS: The current project replicated recent findings that pain, anxiety, and depression are common in individuals with EDS+. The ability to focus and control somatic attention appears to be protective and a potential target for interventions in EDS+.
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Dolor Crónico , Síndrome de Ehlers-Danlos , Trastornos Mentales , Ansiedad , Atención , Dolor Crónico/complicaciones , Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/psicología , Humanos , Trastornos Mentales/complicacionesRESUMEN
OBJECTIVES: The advent of germline testing as a standard-of-care practice for certain tumor types and patients presents unique opportunities and challenges for the field of precision oncology. This article describes strategies to address workforce capacity, organizational structure, and genetics education needs within the US Department of Veterans Affairs (VA) with the expectation that these approaches may be applicable to other health care systems. OBSERVATIONS: Germline information can have health, reproductive, and psychosocial implications for veterans and their family members, which can pose challenges when delivering germline information in the setting of cancer care. Additional challenges include the complexity inherent in the interpretation of germline information, the national shortage of genetics professionals, limited awareness and knowledge about genetic principles among many clinicians, and organizational barriers, such as the inability to order genetic tests and receive results in the electronic health record. These challenges demand thoughtful implementation planning at the health care system level to develop sustainable strategies for the delivery of high-quality genetic services in precision oncology practice. CONCLUSIONS: The VA is uniquely positioned to address the integration of germline genetic testing into precision oncology practice due to its outsized role in treating veterans with cancer, training the health care workforce, and developing, testing, and implementing innovative models of clinical care.
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OBJECTIVES: The aim of this study was to investigate the drug information resources available in community pharmacies in Amman, Jordan. METHODS: A total of 156 private community (retail) pharmacies in different parts of Amman, the capital of Jordan, were recruited by personal contact. Pharmacists at the sample pharmacies completed a self-administered questionnaire that consisted of two sections. The first section elicited the drug information resources available in their pharmacies. The second section presented five mock medicines information scenarios and asked respondents to identify the most suitable information resource to be used from a given list. Answers then were coded and entered into SPSS for Windows for statistical analysis. KEY FINDINGS: All pharmacies had at least one reference book, but most were outdated. The Monthly Index of Medical Specialties (MIMS) was the most commonly found (n = 101; 64.7%), and 40.4% (n = 63) had internet access. Only 19.2% (n = 30) of the respondents reported getting medicines information directly from pharmaceutical companies, usually through pharmaceutical representatives. Most pharmacists could identify appropriate information resources for drug dosing and side effects but did not fare well for medicine identification, drug interactions and primary research evidence. CONCLUSIONS: The quality of drug information resources in private community pharmacies in Amman is far from optimal. This will affect the quality of information provided to patients and prescribers and have an adverse effect on the role that pharmacists can play in the health system in Jordan.
Asunto(s)
Servicios Comunitarios de Farmacia , Servicios de Información sobre Medicamentos , Adulto , Femenino , Humanos , Jordania , Masculino , Persona de Mediana Edad , FarmaciasRESUMEN
INTRODUCTION: Understanding price components for insulin products can help design interventions to improve insulin affordability in low/middle-income countries. METHODS: An adapted WHO/Health Action International standardised methodology was used in Brazil (Rio de Janeiro), China (Hubei and Shaanxi Provinces), Ghana, India (Haryana State), Indonesia and Uganda. Selected insulin products had their prices traced backwards through the supply chain from public and private sector retail outlets in the capital city and a district town, supplemented with key informant interviews. RESULTS: Cumulative mark-ups ranged from 8.7% to 565.8% but the magnitude of mark-ups was country specific and variable within and across sectors and regions. The proportion of the patient price attributed to the manufacturer's selling price varied from 15.0% to 92.0%. Pricing regulations in China, India and Indonesia reduced wholesale and retail mark-ups but did not guarantee low prices. Most countries had removed import duties (Ghana, India, Indonesia, Uganda), but additional tariffs of 3.5% were still applied in Ghana. Value-added tax in the private sector ranged from 5% to 20% across the countries. CONCLUSION: There are no clear trends in the mark-ups applied to insulin or specific differences in the price structure. A uniform approach to improving insulin access through regulating price components is unlikely to be successful, but elimination of duties and taxes, price regulation and greater price transparency could help influence prices and hence affordability.