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High risk features in colorectal adenomatous polyps include size >1 cm and advanced histology: high-grade dysplasia and villous architecture. We investigated whether the diagnostic rates of advanced histology in colorectal adenomatous polyps were similar among institutions across the United States, and if not, could differences be explained by patient age, polyp size, and/or CRC rate. Nine academic institutions contributed data from three pathologists who had signed out at least 100 colorectal adenomatous polyps each from 2018 to 2019 taken from patients undergoing screening colonoscopy. For each case, we recorded patient age and sex, polyp size and location, concurrent CRC, and presence or absence of HGD and villous features. A total of 2700 polyps from 1886 patients (mean age: 61 years) were collected. One hundred twenty-four (5 %) of the 2700 polyps had advanced histology, including 35 (1 %) with HGD and 101 (4 %) with villous features. The diagnostic rate of advanced histology varied by institution from 1.7 % to 9.3 % (median: 4.3 %, standard deviation [SD]: 2.5 %). The rate of HGD ranged from 0 % to 3.3 % (median: 1 %, SD: 1.2 %), while the rate of villous architecture varied from 1 % to 8 % (median: 3.7 %, SD: 2.5 %). In a multivariate analysis, the factor most strongly associated with advanced histology was polyp size >1 cm with an odds ratio (OR) of 31.82 (95 % confidence interval [CI]: 20.52-50.25, p < 0.05). Inter-institutional differences in the rate of polyps >1 cm likely explain some of the diagnostic variance, but pathologic subjectivity may be another contributing factor.
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Pólipos Adenomatosos , Neoplasias Colorrectales , Humanos , Pólipos Adenomatosos/patología , Pólipos Adenomatosos/epidemiología , Pólipos Adenomatosos/diagnóstico , Persona de Mediana Edad , Masculino , Femenino , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/epidemiología , Anciano , Colonoscopía , Pólipos del Colon/patología , Pólipos del Colon/diagnóstico , Pólipos del Colon/epidemiología , Adulto , Estados Unidos/epidemiología , Factores de RiesgoRESUMEN
PURPOSE: This phase Ib/2 trial investigated pembrolizumab-containing trimodality therapy in patients with gastroesophageal junction (GEJ) adenocarcinoma. PATIENTS AND METHODS: Patients with GEJ adenocarcinoma (cT1-3NanyM0) received neoadjuvant pembrolizumab-containing chemoradiation (CROSS regimen) followed by surgical resection and adjuvant pembrolizumab. The primary endpoints were tolerability in the first 16 patients and pathologic complete response [pCR (ypT0N0)]. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). An independent propensity-score-matched cohort (treated with CROSS without immunotherapy) was used for comparison. Exploratory analyses included immune biomarkers in the tumor microenvironment (TME) and plasma. RESULTS: We enrolled 31 eligible patients, of whom 29 received all expected doses of neoadjuvant pembrolizumab and 28 underwent R0 resection. Safety endpoints were met. The primary efficacy endpoint was not met [7/31 (22.6%) achieved pCR]. Patients with high [i.e., combined positive score (CPS) ≥ 10] baseline expression of programmed death (PD)-L1 in the TME had a significantly higher pCR rate than those with low expression [50.0% (4/8) vs. 13.6% (3/22); P = 0.046]. Patients with high PD-L1 expression also experienced longer PFS and OS than propensity-score-matched patients. Among trial patients with PD-L1 CPS < 10, unprespecified analysis explored whether extracellular vesicles (EV) could identify further responders: an elevated plasma level of PD-L1-expressing EVs was significantly associated with higher pCR. CONCLUSIONS: Adding pembrolizumab to trimodality therapy showed acceptable tolerability but did not meet the pre-specified pCR endpoint. Exploratory analyses suggested that high PD-L1 expression in the TME and/or on EVs may identify patients most likely to achieve tumor response.
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Adenocarcinoma , Antineoplásicos Inmunológicos , Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos/efectos adversos , Antígeno B7-H1/metabolismo , Neoplasias Esofágicas , Unión Esofagogástrica/patología , Humanos , Terapia Neoadyuvante , Microambiente TumoralRESUMEN
Saccular aneurysms (SAs) are focal outpouchings from the lateral wall of an artery. Depending on their morphology and location, minimally invasive treatment options include coil embolization, flow diverter stents, stent-assisted coiling, and liquid embolics. Many drawbacks are associated with these treatment options including recanalization, delayed healing, rebleeding, malpositioning of the embolic or stent, stent stenosis, and even rupture of the SA. To overcome these drawbacks, a nanoclay-based shear-thinning hydrogel (STH) is developed for the endovascular treatment of SAs. Extensive in vitro testing is performed to optimize STH performance, visualization, injectability, and endothelialization in cell culture. Femoral artery saccular aneurysm models in rats and in pigs are created to test stability, efficacy, immune response, endothelialization, and biocompatibility of STH in both ruptured and unruptured SA. Fluoroscopy and computed tomography imaging consistently confirmed SA occlusion without recanalization, migration, or nontarget embolization; STH is also shown to outperform coil embolization of porcine aneurysms. In pigs with catastrophic bleeding due to SA rupture, STH is able to achieve instant hemostasis rescuing the pigs in long-term survival experiments. STH is a promising semisolid iodinated embolic agent that can change the standard of medical practice and potentially save lives.
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Aneurisma Roto , Procedimientos Endovasculares , Aneurisma Intracraneal , Aneurisma Roto/cirugía , Aneurisma Roto/terapia , Animales , Aneurisma Intracraneal/cirugía , Aneurisma Intracraneal/terapia , Ratas , Estudios Retrospectivos , Stents , Porcinos , Resultado del TratamientoRESUMEN
BACKGROUND: FGFR2 genomic alterations are observed in 10-20% of cholangiocarcinoma (CCA). Although FGFR2 fusions are an important actionable target, FGFR2 protein expression has not been thoroughly characterized. AIMS: To evaluate FGFR2 protein expression in cholangiocarcinoma harboring FGFR2 genomic alterations. METHODS: FGFR2 protein expression was evaluated in 99 CCA cases with two different antibodies. FGFR2 genomic alterations were confirmed via next-generating sequencing (NGS) or FISH. Primary objective was to determine the specificity and sensitivity of FGFR2 immunohistochemistry staining for detecting FGFR2 genomic alterations. Secondary objectives included overall FGFR2 immunohistochemistry staining in CCA patients, and evaluation of whether FGFR2 expression correlates with clinical outcomes including overall survival (OS), progression-free survival (PFS), and time-to-tumor recurrence (TTR). RESULTS: Immunohistochemistry staining with two antibodies against FGFR2, FPR2-D, and clone 98706 showed high accuracy (78.7% and 91.9%) and specificity (82.9% and 97.7%), and moderate sensitivity (53.9% and 57.1%), respectively, when compared with the standard methods for detecting FGFR2 genomic alterations. In a median follow-up of 72 months, there were no statistically significant differences in OS, PFS, and TTR, for patients with positive or negative FGFR2 staining. CONCLUSION: FGFR2 protein expression by immunohistochemistry has high specificity and therefore could be used to imply the presence of FGFR2 genomic alterations in the context of a positive test. In the case of a negative test, NGS or FISH would be necessary to ascertain cases with FGFR2 genomic alterations.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , Genómica , Humanos , Inmunohistoquímica , Recurrencia Local de Neoplasia/patología , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismoRESUMEN
BACKGROUND AND AIMS: Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin-dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive. APPROACH AND RESULTS: Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity, and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy attributable to autophagy-induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine. CONCLUSIONS: As such, these data provide robust preclinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias del Sistema Biliar/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Autofagia/efectos de los fármacos , Neoplasias del Sistema Biliar/mortalidad , Neoplasias del Sistema Biliar/patología , Cisplatino/farmacología , Cisplatino/uso terapéutico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Sinergismo Farmacológico , Humanos , Ratones , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
Embolization is a catheter-based minimally invasive procedure that deliberately occludes diseased blood vessels for treatment purposes. A novel silk-based embolic material (SEM) that is developed and optimized to provide tandem integration of both embolization and the delivery of therapeutics is reported. Natural silk is processed into fibroin proteins of varying lengths and is combined with charged nanoclay particles to allow visibility and injectability using clinical catheters as small as 600 µm in diameter at lengths >100 cm. SEMs loaded with fluorochrome labeled bovine albumin and Nivolumab, which is among the most used immunotherapy drugs worldwide, demonstrate a sustained release profile in vitro over 28 days. In a porcine renal survival model, SEMs with labeled albumin and Nivolumab successfully embolize porcine arteries without recanalization and lead to the delivery of both albumin and Nivolumab into the interstitial space of the renal cortex. Mechanistically, it is shown that tissue delivery is most optimal when the internal elastic membrane of the embolized artery is disrupted. SEM is a potential next-generation multifunctional embolic agent that can achieve embolization and deliver a wide range of therapeutics to treat vascular diseases including tumors.
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Embolización Terapéutica , Seda , Animales , Arterias , Catéteres , Bovinos , Sistemas de Liberación de Medicamentos , Embolización Terapéutica/métodos , PorcinosRESUMEN
OBJECTIVES: Misplaced epithelium in adenomas can occasionally be difficult to distinguish from invasive adenocarcinoma. We evaluated interobserver variability in the assessment of left-sided colon polypectomies for pseudoinvasion versus invasive adenocarcinoma and further investigated relevant histological findings. METHODS: 28 consecutive left-sided colon polyps with the keywords "pseudoinvasion", "epithelial misplacement", "herniation", "prolapse" or "invasive adenocarcinoma" were collected from 28 patients and reviewed by eight gastrointestinal pathologists. Participants assessed stromal hemosiderin, lamina propria/eosinophils surrounding glands, desmoplasia, high grade dysplasia/intramucosal adenocarcinoma and margin status and rendered a diagnosis of pseudoinvasion, invasive adenocarcinoma, or both. RESULTS: Agreement among pathologists was substantial for desmoplasia (κ=0.70), high grade dysplasia/intramucosal adenocarcinoma (κ=0.66), invasive adenocarcinoma (κ=0.63) and adenocarcinoma at the margin (κ=0.65). There was moderate agreement for hemosiderin in stroma (κ=0.53) and prolapse/pseudoinvasion (κ=0.50). Agreement was low for lamina propria/eosinophils around glands (κ=0.12). For invasive adenocarcinoma, seven or more pathologists agreed in 24 of 28 cases (86%), and there was perfect agreement in 19/28 cases (68%). For pseudoinvasion, seven or more pathologists agreed in 19 of 28 cases (68%), and there was perfect agreement in 16/28 cases (57%). CONCLUSION: Moderate to substantial, though imperfect, agreement was achieved in the distinction of pseudoinvasion from invasive carcinoma.
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Adenocarcinoma , Carcinoma , Neoplasias Colorrectales , Adenocarcinoma/patología , Hemosiderina , Humanos , Hiperplasia , Variaciones Dependientes del ObservadorRESUMEN
Amyloidosis is a group of conditions defined by extracellular deposition of insoluble proteins that can lead to multiorgan dysfunction and failure. The systemic form of the disease is often associated with a plasma cell dyscrasia but may also occur in the setting of chronic inflammation, long-term dialysis, malignancy, or multiple hereditary conditions. Localized forms of the disease most often involve the skin, tracheobronchial tree, and urinary tract and typically require tissue sampling for diagnosis, as they may mimic many conditions including malignancy at imaging alone. Advancements in MRI and nuclear medicine have provided greater specificity for the diagnosis of amyloidosis involving the central nervous system and heart, potentially obviating the need for biopsy of the affected organ in certain circumstances. Specifically, a combination of characteristic findings at noninvasive cardiac MRI and skeletal scintigraphy in patients without an underlying plasma cell dyscrasia is diagnostic for cardiac transthyretin amyloidosis. Histologically, the presence of amyloid is denoted by staining with Congo red and a characteristic apple green birefringence under polarized light microscopy. The imaging features of amyloid vary across each organ system but share some common patterns, such as soft-tissue infiltration and calcification, that may suggest the diagnosis in the appropriate clinical context. The availability of novel therapeutics that target amyloid protein fibrils such as transthyretin highlights the importance of early diagnosis. Online supplemental material is available for this article. ©RSNA, 2021.
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Neuropatías Amiloides Familiares , Amiloide , Biopsia , Rojo Congo , Humanos , Coloración y EtiquetadoRESUMEN
Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum ranging from simple steatosis to histologically defined hepatocyte injury and inflammatory changes that define steatohepatitis (NASH), and increase risk for fibrosis. Although zonal differences in NASH have not been systematically studied, periportal involvement has been associated with worse metabolic outcomes and more hepatic fibrosis as compared to pericentral disease. These data suggest that hepatic zonation of disease may influence the diversity of clinical presentations. Similarly, several randomized clinical trials suggest a differential response based on zonation of disease, with preferential effects on periportal (cysteamine) or pericentral disease (obeticholic acid, pioglitazone). Intriguingly, morphogenic pathways known to affect zonal development and maintenance - WNT/ß-Catenin, Hedgehog, HIPPO/Yap/TAZ and Notch - have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient-specific activation of these pathways may explain the variability in clinical presentation, and the zone-specific response observed in clinical trials.
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Enfermedad del Hígado Graso no Alcohólico , Hepatocitos , Humanos , Hígado/patología , Cirrosis Hepática/patología , Enfermedad del Hígado Graso no Alcohólico/patología , PioglitazonaRESUMEN
We present a case of haemorrhagic enterocolitis in a patient with SARS-CoV-2 who recovered from respiratory failure after support with venovenous extracorporeal membrane oxygenation. We describe clinicopathological features consistent with the systemic coinfection/reactivation of cytomegalovirus (CMV) concurrent with COVID-19 infection and the protracted clinical course of resolution of gastrointestinal inflammation after the treatment of CMV infection. Stool PCR, abdominal CT perfusion scan and histological examination of ileal and colonic tissues excluded enterocolitis secondary to other causes of infection (common viral, bacterial and protozoal gastrointestinal pathogens), macrovascularand microvascular ischaemia and classic inflammatory bowel disease, respectively. We propose possible synergistic pathophysiologic mechanisms for enterocolitis complicating severe COVID-19 infection: (1) T lymphocyte depletion and immune response dysregulation, (2) use of immunomodulators in the management of severe COVID-19 infection and (3) high concentration of ACE-2 receptors for COVID-19 virus in the gastrointestinal tract.
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COVID-19/complicaciones , Coinfección/virología , Infecciones por Citomegalovirus/complicaciones , Enterocolitis/complicaciones , Hemorragia Gastrointestinal/virología , COVID-19/terapia , Diarrea/virología , Enterocolitis/virología , Oxigenación por Membrana Extracorpórea , Femenino , Humanos , Persona de Mediana Edad , SARS-CoV-2RESUMEN
The diagnosis of inflammatory bowel disease (IBD)-associated dysplasia is challenging, and past studies have demonstrated considerable interobserver variability in such diagnoses. This study aimed to assess interobserver agreement in IBD dysplasia diagnoses among subspecialty GI pathologists and to explore the impact of mentorship on diagnostic variability. Twelve GI pathologist mentees and 7 GI pathologist mentors reviewed 163 digitized slides. Participants rendered a diagnosis of negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, or high-grade dysplasia and provided a confidence level for each case. Interobserver agreement and reliability were assessed using Cohen's and Fleiss' kappa (κ) statistics and intraclass correlation coefficient (ICC) analysis. The overall κ coefficient was 0.42 (95% CI: 0.38-0.46). The overall ICC was 0.67 (95% CI: 0.62-0.72). Κ coefficients ranged from 0.31 to 0.49 for mentor/mentee pairs and from 0.34 to 0.55 for pairs of mentees of the same mentor. The combined κ coefficient was 0.44 (95% CI: 0.39-0.48) for all mentees and 0.39 (95% CI: 0.34-0.43) for all mentors. Common features in low agreement cases included mucosal atrophy, areas of stark contrast, serrations, decreased goblet cells, absent surface epithelium, and poor orientation. Participants were confident in most diagnoses, and increased confidence levels generally correlated with higher interobserver agreement. Interobserver agreement among subspecialist GI pathologists in this curated cohort of IBD dysplasia cases was fair to moderate. Mentorship during GI pathology fellowship does not appear to be a significant factor contributing to interobserver variability, but increased experience also does not seem to improve interobserver agreement.
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Esófago de Barrett/patología , Enfermedades Inflamatorias del Intestino/patología , Variaciones Dependientes del Observador , Patólogos , Adolescente , Adulto , Esófago de Barrett/diagnóstico , Niño , Femenino , Tracto Gastrointestinal/patología , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Masculino , Mentores , Adulto JovenRESUMEN
BACKGROUND & AIMS: The hepatocyte Notch pathway is a pathogenic factor in non-alcoholic steatohepatitis (NASH)-associated fibrosis, but its role in hepatocellular carcinoma (HCC) is less well defined. Herein, we aimed to characterize the molecular and clinical features of Notch-active human HCC, and to investigate the mechanisms by which Notch affects NASH-driven HCC. METHODS: Using a 14-gene Notch score, we stratified human HCCs from multiple comprehensively profiled datasets. We performed gene set enrichment analyses to compare Notch-active HCCs with published HCC subtype signatures. Next, we sorted Notch-active hepatocytes from Notch reporter mice for RNA sequencing and characterized Notch-active tumors in an HCC model combining a carcinogen and a NASH-inducing diet. We used genetic mouse models to manipulate hepatocyte Notch to investigate the sufficiency and necessity of Notch in NASH-driven tumorigenesis. RESULTS: Notch-active signatures were found in ~30% of human HCCs that transcriptionally resemble cholangiocarcinoma-like HCC, exhibiting a lack of activating CTNNB1 (ß-catenin) mutations and a generally poor prognosis. Endogenous Notch activation in hepatocytes is associated with repressed ß-catenin signaling and hepatic metabolic functions, in lieu of increased interactions with the extracellular matrix in NASH. Constitutive hepatocyte Notch activation is sufficient to induce ß-catenin-inactive HCC in mice with NASH. Notch and ß-catenin show a pattern of mutual exclusivity in carcinogen-induced HCC; in this mouse model, chronic blockade of Notch led to ß-catenin-dependent tumor development. CONCLUSIONS: Notch activity characterizes a distinct HCC molecular subtype with unique histology and prognosis. Sustained Notch signaling in chronic liver diseases can drive tumor formation without acquiring specific genomic driver mutations. LAY SUMMARY: The Notch signaling pathway is known to be involved in the pathogenesis of liver fibrosis. However, its role in liver cancer has not been well defined. Herein, we show that Notch activity is increased in a subset of liver cancers and is associated with poor outcomes. We also used a mouse model to show that aberrant Notch activity can drive cancer progression in obese mice.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Receptores Notch/genética , Vía de Señalización Wnt/genética , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinoma Hepatocelular/patología , Modelos Animales de Enfermedad , Femenino , Hepatocitos/metabolismo , Humanos , Cirrosis Hepática/genética , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Pronóstico , Receptores Notch/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Vascular embolization is a life-saving minimally invasive catheter-based procedure performed to treat bleeding vessels. Through these catheters, numerous metallic coils are often pushed into the bleeding artery to stop the blood flow. While there are numerous drawbacks to coil embolization, physician expertise, availability of these coils, and their costs further limit their use. Here, a novel blood-derived embolic material (BEM) with regenerative properties, that can achieve instant and durable intra-arterial hemostasis regardless of coagulopathy, is developed. In a large animal model of vascular embolization, it is shown that the BEM can be prepared at the point-of-care within 26 min using fresh blood, it can be easily delivered using clinical catheters to embolize renal and iliac arteries, and it can achieve rapid hemostasis in acutely injured vessels. In swine arteries, the BEM increases cellular proliferation, angiogenesis, and connective tissue deposition, suggesting vessel healing and durable vessel occlusion. The BEM has significant advantages over embolic materials used today, making it a promising new tool for embolization.
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Arterias , Materiales Biocompatibles/farmacología , Sangre , Catéteres , Embolización Terapéutica/instrumentación , Animales , Proliferación Celular/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , PorcinosRESUMEN
Transcatheter embolization is a minimally invasive procedure that uses embolic agents to intentionally block diseased or injured blood vessels for therapeutic purposes. Embolic agents in clinical practice are limited by recanalization, risk of non-target embolization, failure in coagulopathic patients, high cost, and toxicity. Here, a decellularized cardiac extracellular matrix (ECM)-based nanocomposite hydrogel is developed to provide superior mechanical stability, catheter injectability, retrievability, antibacterial properties, and biological activity to prevent recanalization. The embolic efficacy of the shear-thinning ECM-based hydrogel is shown in a porcine survival model of embolization in the iliac artery and the renal artery. The ECM-based hydrogel promotes arterial vessel wall remodeling and a fibroinflammatory response while undergoing significant biodegradation such that only 25% of the embolic material remains at 14 days. With its unprecedented proregenerative, antibacterial properties coupled with favorable mechanical properties, and its superior performance in anticoagulated blood, the ECM-based hydrogel has the potential to be a next-generation biofunctional embolic agent that can successfully treat a wide range of vascular diseases.
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Arterias/efectos de los fármacos , Arterias/fisiopatología , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Embolización Terapéutica/métodos , Hidrogeles/química , Nanocompuestos/química , Animales , Arterias/patología , Matriz Extracelular/química , Resistencia al Corte , Porcinos , Remodelación Vascular/efectos de los fármacosRESUMEN
PURPOSE: NUC1031 is a first-in-class ProTide, that is a gemcitabine pro-drug designed to overcome putative mechanisms of resistance, including decreased expression of hENT/hCNT transporters, absence of activating enzymes such as deoxycytidine kinase (dCK) and presence of degrading enzymes such as cytidine deaminase (CDA). We undertook comprehensive pre-clinical evaluation of NUC1031 in biliary tract cancer (BTC) models, given that gemcitabine/cisplatin is a standard first-line therapy in advanced BTC. METHODS: Here, we compared the in vitro activity of NUC1031 in comparison to gemcitabine, validate putative mechanism(s) of action, assessed potential biomarkers of sensitivity or resistance, and performed combination studies with cisplatin. We also evaluated the in vivo efficacy of NUC1031 and gemcitabine using a CDA-high cholangiocarcinoma patient-derived xenograft (PDX) model. RESULTS: In a panel of BTC cell lines (N = 10), NUC1031 had less potency than gemcitabine in multiple cellular assays. NUC1031 did not demonstrate evidence of greater synergy over gemcitabine in combination with cisplatin. Surprisingly, efficacy of both gemcitabine and NUC1031 was not found to be correlated with hENT/hCTN, dCK or CDA transcript levels. Gemcitabine and NUC1031 showed equivalent efficacy in a CDA-high PDX model in vivo contradicting the primary rationale of NUC1031 design. CONCLUSION: NUC1031 did not exhibit evidence of superior activity over gemcitabine, as a single-agent, or in combination with cisplatin, in either our in vivo or in vitro BTC models. Given that the largest Phase 3 study (ClinicalTrials.gov: NCT0314666) to date in BTC is underway (N = 828) comparing NUC1031/cisplatin to gemcitabine/cisplatin, our results suggest that a more conservative clinical evaluation path would be more appropriate.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias del Sistema Biliar/tratamiento farmacológico , Sinergismo Farmacológico , Animales , Apoptosis , Neoplasias del Sistema Biliar/patología , Proliferación Celular , Cisplatino/administración & dosificación , Citidina Monofosfato/administración & dosificación , Citidina Monofosfato/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
We report a case of an adult male patient with multifocal urinary bladder paragangliomas, which were negative on Ga-DOTATATE PET/CT scan, but positive on I-MIBG SPECT/CT scan. While the Ga-DOTA analog PET/CT exhibits superior performance in diagnosis and staging of pheochromocytoma and paraganglioma, our case demonstrates negative somatostatin receptor expression in this rare entity and indicates that I-MIBG SPECT/CT still plays a vital role in characterization of bladder paraganglioma.
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3-Yodobencilguanidina/metabolismo , Compuestos Organometálicos/metabolismo , Paraganglioma/diagnóstico , Paraganglioma/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen , Neoplasias de la Vejiga Urinaria/metabolismo , Transporte Biológico , Humanos , Masculino , Persona de Mediana Edad , Receptores de Somatostatina/metabolismoRESUMEN
Despite recent advancements in therapeutic options for advanced hepatobiliary cancers, there remains an unmet need for innovative systemic treatments. Immunotherapy has shown an ability to provide prolonged clinical benefit, but this benefit remains limited to a small subset of patients. Numerous ongoing endeavors are investigating novel immunotherapy concepts. Immunotherapies that have demonstrated clinical efficacy in hepatobiliary cancers include PD-1 inhibitor therapy and CTLA-4 inhibitor therapy. Novel immunotherapy concepts include targeting emerging checkpoint proteins, bispecific T-cell engagers, combinatorial trials with checkpoint inhibitors, oncolytic virotherapy and chimeric antigen receptor T cells. The goal for these new treatment strategies is to achieve a meaningful expansion of patients deriving prolonged clinical benefit from immunotherapy.
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Anticuerpos Monoclonales/uso terapéutico , Neoplasias del Sistema Biliar/terapia , Carcinoma Hepatocelular/terapia , Inmunoterapia Adoptiva , Inmunoterapia/métodos , Neoplasias Hepáticas/terapia , Linfocitos T/inmunología , Animales , Neoplasias del Sistema Biliar/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Carcinoma Hepatocelular/inmunología , Humanos , Inmunoterapia/tendencias , Neoplasias Hepáticas/inmunología , Viroterapia Oncolítica , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T/trasplanteRESUMEN
Immune checkpoint inhibitors (ICPIs) are novel therapeutic agents targeting a variety of cancers by enhanced T cell activation. Immune-related adverse events (irAEs) commonly occur with ICPI use and can affect multiple organ systems including the gastrointestinal tract. Due to irAEs, the use of ICPIs is limited in autoimmune diseases. We present a case of microscopic colitis diagnosed after the initiation of nivolumab and a case of ipilimumab colitis and Clostridium difficile in the setting of Crohn's colitis.
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BACKGROUND: Patients with solid organ transplants (SOTs) have been excluded from programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor clinical trials due to concern for allograft rejection. The use of immune checkpoint inhibitor therapy remains controversial in transplant patients. METHODS: A retrospective pilot evaluation was conducted to assess the safety and efficacy of PD-1 inhibitors in patients with liver transplantation (LT). The primary endpoint was the rate of allograft rejection. Secondary endpoints included overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Translational objectives included evaluation of tumor PD-L1, tumor infiltrating lymphocytes (TILs) and allograft PD-L1 expression. RESULTS: Seven metastatic cancer patients with a history of LT who received PD-1 inhibitor therapy were included [hepatocellular carcinoma (HCC), n=5; melanoma, n=2]. Rejection was observed in 2 of 7 patients. When rejection occurs it appears to be an early event with a median time to rejection of 24 days in our cohort. One patient achieved a complete response (CR), 3 patients had progressive disease (PD) and 3 patients discontinued therapy prior to restaging assessments. Two of five patients with available tissue had PD-L1 expression in the allograft and both developed rejection. One of five evaluable patients had abundant TILs. Two of five evaluable patients had PD-L1 tumor staining. The single patient with both abundant TILs and PD-L1 staining obtained a response. The median OS and PFS were 1.1 (0.3-21.1) and 1.8 (0.7-21.1) months, respectively. CONCLUSIONS: In this pilot evaluation both preliminary efficacy (1 of 4) and allograft rejection (2 of 7) were exhibited in evaluable patients. Larger, prospective trials are needed to elucidate optimal patient selection.