RESUMEN
BACKGROUND: In 2014, technetium-99m tilmanocept (TcTM) replaced technetium-99m sulfur colloid (TcSC) as the standard lymphoscintigraphy (LS) mapping agent in melanoma patients undergoing sentinel lymph node biopsy (SLNB). The aim of this study was to examine differences in mapping time, intra-operative identification of sentinel lymph node (SLN), and false negative rate (FNR) between patients who underwent SLNB with TcTM compared to TcSC. METHODS: Patients who underwent SLNB between 2010 and 2018 were retrospectively identified. Patient demographic, tumor, and imaging data was stratified by receipt of TcSC (n = 258) or TcTM (n = 133). Student's t test and χ2 test were used to compare characteristics and outcomes. RESULTS: Both cohorts were similar in demographic, primary tumor characteristics, and total number of SLN identified (TcTM 3.56 vs. TcSC 3.28, p = 0.244). TcTM was associated with significantly shorter LS mapping times (51.8 vs. 195.1 min, p < 0.01). There was no significant difference in the number of patients with positive SLN (TcTM 11.3 vs. TcSC 17.4%, p = 0.109) and the FNR was similar between both groups (TcTM 25% vs. TcSC 22%). CONCLUSION: TcTM was associated with significantly shorter LS mapping time while identifying similar numbers of SLN. Our results support further study to ensure similar FNR and oncologic outcomes between agents.
Asunto(s)
Linfocintigrafia/métodos , Melanoma/patología , Recurrencia Local de Neoplasia/patología , Radiofármacos/metabolismo , Ganglio Linfático Centinela/patología , Pentetato de Tecnecio Tc 99m/metabolismo , Azufre Coloidal Tecnecio Tc 99m/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melanoma/diagnóstico por imagen , Melanoma/metabolismo , Melanoma/cirugía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Estudios Retrospectivos , Ganglio Linfático Centinela/diagnóstico por imagen , Ganglio Linfático Centinela/metabolismo , Ganglio Linfático Centinela/cirugía , Biopsia del Ganglio Linfático Centinela , Adulto JovenRESUMEN
The goal of a gastric cancer operation is a microscopically negative resection margin and D2 lymphadenectomy. Minimally invasive techniques (laparoscopic and robotic) have been proven to be equivalent for oncologic care, yet with faster recovery. Endoscopic mucosal resection can be used for T1a N0 tumor resection. Better understanding of hereditary gastric cancer and molecular subtypes has led to specialized recommendations for MSI-high tumors and patients with pathogenic CDH1 mutations. In the future, surgical management will support minimally invasive approaches and personalized cancer care based on subtype.
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Neoplasias Gástricas , Humanos , Manejo de la Enfermedad , Gastrectomía/métodos , Laparoscopía/métodos , Escisión del Ganglio Linfático/métodos , Procedimientos Quirúrgicos Robotizados/métodos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugíaRESUMEN
[URE3] is a prion of the nitrogen catabolism controller, Ure2p, and [PSI+] is a prion of the translation termination factor Sup35p in S. cerevisiae. Btn2p cures [URE3] by sequestration of Ure2p amyloid filaments. Cur1p, paralogous to Btn2p, also cures [URE3], but by a different (unknown) mechanism. We find that an array of mutations impairing proteasome assembly or MG132 inhibition of proteasome activity result in loss of [URE3]. In proportion to their prion-curing effects, each mutation affecting proteasomes elevates the cellular concentration of the anti-prion proteins Btn2 and Cur1. Of >4,600 proteins detected by SILAC, Btn2p was easily the most overexpressed in a pre9Δ (α3 core subunit) strain. Indeed, deletion of BTN2 and CUR1 prevents the prion-curing effects of proteasome impairment. Surprisingly, the 15 most unstable yeast proteins are not increased in pre9Δ cells suggesting altered proteasome specificity rather than simple inactivation. Hsp42, a chaperone that cooperates with Btn2 and Cur1 in curing [URE3], is also necessary for the curing produced by proteasome defects, although Hsp42p levels are not substantially altered by a proteasome defect. We find that pre9Δ and proteasome chaperone mutants that most efficiently lose [URE3], do not destabilize [PSI+] or alter cellular levels of Sup35p. A tof2 mutation or deletion likewise destabilizes [URE3], and elevates Btn2p, suggesting that Tof2p deficiency inactivates proteasomes. We suggest that when proteasomes are saturated with denatured/misfolded proteins, their reduced degradation of Btn2p and Cur1p automatically upregulates these aggregate-handling systems to assist in the clean-up.
Asunto(s)
Sistemas de Transporte de Aminoácidos/metabolismo , Glutatión Peroxidasa/metabolismo , Chaperonas Moleculares/metabolismo , Priones/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Amiloide/metabolismo , Citoplasma/metabolismo , Proteínas Fúngicas/metabolismo , Glutatión Peroxidasa/genética , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/genética , Factores de Terminación de Péptidos/genética , Factores de Terminación de Péptidos/metabolismo , Proteínas Priónicas/metabolismo , Priones/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
BACKGROUND: Glioblastoma (GBM) is the most common adult primary brain tumor. Multimodal treatment is empiric and prognosis remains poor. Recurrent PIK3CA missense mutations (PIK3CAmut) in GBM are restricted to three functional domains: adaptor binding (ABD), helical, and kinase. Defining how these mutations influence gliomagenesis and response to kinase inhibitors may aid in the clinical development of novel targeted therapies in biomarker-stratified patients. METHODS: We used normal human astrocytes immortalized via expression of hTERT, E6, and E7 (NHA). We selected two PIK3CAmut from each of 3 mutated domains and induced their expression in NHA with (NHARAS) and without mutant RAS using lentiviral vectors. We then examined the role of PIK3CAmut in gliomagenesis in vitro and in mice, as well as response to targeted PI3K (PI3Ki) and MEK (MEKi) inhibitors in vitro. RESULTS: PIK3CAmut, particularly helical and kinase domain mutations, potentiated proximal PI3K signaling and migration of NHA and NHARAS in vitro. Only kinase domain mutations promoted NHA colony formation, but both helical and kinase domain mutations promoted NHARAS tumorigenesis in vivo. PIK3CAmut status had minimal effects on PI3Ki and MEKi efficacy. However, PI3Ki/MEKi synergism was pronounced in NHA and NHARAS harboring ABD or helical mutations. CONCLUSION: PIK3CAmut promoted differential gliomagenesis based on the mutated domain. While PIK3CAmut did not influence sensitivity to single agent PI3Ki, they did alter PI3Ki/MEKi synergism. Taken together, our results demonstrate that a subset of PIK3CAmut promote tumorigenesis and suggest that patients with helical domain mutations may be most sensitive to dual PI3Ki/MEKi treatment.