RESUMEN

PURPOSE: To assess the efficacy of a gelatin stent (XEN 45 Gel Stent; Allergan) implant in advanced glaucoma eyes that have failed prior aqueous shunt implantation. METHODS: We retrospectively reviewed 6 patients with refractory glaucoma, defined as persistently high IOP (> 21 mmHg) despite taking at least 3 IOP-lowering medications subsequent to undergoing a glaucoma drainage device (GDD) with or without a second GDD or cilioablative procedure. Eyes with previous failed GDD underwent subconjunctival 0.3 cc (0.4 mg/ml) mitomycin C, tenonectomy, and placement of an ab- externo XEN stent. The outcome measures included change in IOP and the number of glaucoma medications. Success was defined as patients achieving an IOP ≤ 18 mmHg with a percentage reduction of 25% or 15 mmHg and 40% mean IOP reduction from baseline while taking the same number or fewer medications. RESULTS: All six eyes with age of 77.6 ± 7.82 years who underwent XEN implantation following previous GDD surgery had primary open-angle glaucoma. The IOP decreased significantly from 32.33 ± 5.99 to 12.67 ± 3.27 mmHg (p < 0.001) with a follow-up of 13.9 ± 2 (11.7-16.7) months. Visual acuity and visual field remained stable after XEN placement. Compared to the baseline number of medications of 4.2 ± 0.8, all medication was discontinued except in one eye on two drops at the end of the follow-up. The overall surgical success rate was 100%. No complications, needling, or additional procedures were required. CONCLUSION: This study described successful implantation of the XEN stent following failed GDD. XEN Gel stent implantation associated with mitomycin C and tenonectomy can be considered a viable surgical option for patients with a history of previously failed tube shunt requiring further IOP lowering.

Asunto(s)

Implantes de Drenaje de Glaucoma , Presión Intraocular , Stents , Agudeza Visual , Humanos , Estudios Retrospectivos , Masculino , Femenino , Presión Intraocular/fisiología , Anciano , Agudeza Visual/fisiología , Anciano de 80 o más Años , Glaucoma de Ángulo Abierto/cirugía , Glaucoma de Ángulo Abierto/fisiopatología , Glaucoma/cirugía , Glaucoma/fisiopatología , Implantación de Prótesis/métodos , Persona de Mediana Edad , Resultado del Tratamiento , Gelatina/uso terapéutico , Estudios de Seguimiento

RESUMEN

Triple-negative breast cancer (TNBC) is characterized by the absence of the estrogen receptor, progesterone receptor, and receptor tyrosine kinase HER2 expression. Due to the limited number of FDA-approved targeted therapies for TNBC, there is an ongoing need to understand the molecular underpinnings of TNBC for the development of novel combinatorial treatment strategies. This study evaluated the role of the MerTK receptor tyrosine kinase on proliferation and invasion/metastatic potential in TNBC. Immunohistochemical analysis demonstrated MerTK expression in 58% of patient-derived TNBC xenografts. The stable overexpression of MerTK in human TNBC cell lines induced an increase in proliferation rates, robust in vivo tumor growth, heightened migration/invasion potential, and enhanced lung metastases. NanoString nCounter analysis of MerTK-overexpressing SUM102 cells (SUM102-MerTK) revealed upregulation of several signaling pathways, which ultimately drive cell cycle progression, reduce apoptosis, and enhance cell survival. Proteomic profiling indicated increased endoglin (ENG) production in SUM102-MerTK clones, suggesting that MerTK creates a conducive environment for increased proliferative and metastatic activity via elevated ENG expression. To determine ENG's role in increasing proliferation and/or metastatic potential, we knocked out ENG in a SUM102-MerTK clone with CRISPR technology. Although this ENG knockout clone exhibited similar in vivo growth to the parental SUM102-MerTK clone, lung metastasis numbers were significantly decreased ~4-fold, indicating that MerTK enhances invasion and metastasis through ENG. Our data suggest that MerTK regulates a unique proliferative signature in TNBC, promoting robust tumor growth and increased metastatic potential through ENG upregulation. Targeting MerTK and ENG simultaneously may provide a novel therapeutic approach for TNBC patients.

Asunto(s)

Proliferación Celular , Neoplasias de la Mama Triple Negativas , Tirosina Quinasa c-Mer , Humanos , Tirosina Quinasa c-Mer/metabolismo , Tirosina Quinasa c-Mer/genética , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Animales , Femenino , Ratones , Línea Celular Tumoral , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica , Endoglina/metabolismo , Endoglina/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Metástasis de la Neoplasia , Transducción de Señal , Apoptosis/genética

RESUMEN

ABSTRACT: Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial. At a median follow-up of 7.5 years, there is no difference in the median PFS of BR compared with BVR (5.5 vs 6.4 years; hazard ratio [HR], 0.90; 90% confidence interval [CI], 0.70-1.16). There were no unexpected additional toxicities with BVR treatment compared with BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide did not significantly improve PFS, with median PFS in R vs LR (5.9 vs 7.2 years; HR, 0.84; 90% CI, 0.62-1.15). Most patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with R alone after BR. Nonetheless, the >5-year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by R maintenance as highly effective initial therapy for older patients with MCL. This trial was registered at www.clinicaltrials.gov as #NCT01415752.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Clorhidrato de Bendamustina , Bortezomib , Lenalidomida , Linfoma de Células del Manto , Quimioterapia de Mantención , Rituximab , Humanos , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/uso terapéutico , Bortezomib/administración & dosificación , Bortezomib/uso terapéutico , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/mortalidad , Linfoma de Células del Manto/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano de 80 o más Años , Adulto , Quimioterapia de Inducción , Supervivencia sin Progresión

RESUMEN

BACKGROUND: Epithelial ingrowth is a rare but potentially sight-threatening complication caused by the invasion of corneal or conjunctival epithelial cells into the eye during ocular surgeries. DMEK is emerging as a widely used surgery for endothelial keratoplasty with its improved safety profile. We describe a case of epithelial ingrowth in the graft-host interface after uneventful DMEK associated with vitreous prolapse in the anterior chamber. CASE PRESENTATION: An 81-year-old female with Fuchs endothelial dystrophy underwent DMEK for corneal decompensation following cataract surgery. During the DMEK procedure, vitreous prolapse was observed around the intraocular lens (IOL). Her early postoperative course was unremarkable, but a dense paracentral interface opacity was observed during the 3-month follow-up. The area of epithelial ingrowth was imaged with optical coherence tomography (OCT) as a uniform nodule with a discrete increase in interface hyperreflectivity. A low-energy YAG laser was applied to remove the opacity. She maintained good vision and clear cornea without reoccurrence after treatment. CONCLUSIONS: We propose that, in addition to the introduction of epithelial cells during surgery, vitreous retention in the anterior chamber may be a risk factor by providing a scaffold that potentially aggravates epithelial ingrowth in DMEK. Our case demonstrated that early YAG intervention may disrupt interface epithelial cell growth, and the transmitted laser energy may fragment the scaffold vitreous noninvasively.

Asunto(s)

Queratoplastia Endotelial de la Lámina Limitante Posterior , Distrofia Endotelial de Fuchs , Humanos , Femenino , Anciano de 80 o más Años , Lámina Limitante Posterior/cirugía , Endotelio Corneal , Queratoplastia Endotelial de la Lámina Limitante Posterior/métodos , Complicaciones Posoperatorias/cirugía , Distrofia Endotelial de Fuchs/cirugía , Trastornos de la Visión , Prolapso , Estudios Retrospectivos

RESUMEN

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

Asunto(s)

Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide de Fase Crónica , Humanos , Crisis Blástica/inducido químicamente , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/genética , Inhibidores de Proteínas Quinasas/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Cromosoma Filadelfia , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Proteínas de Fusión bcr-abl/genética

RESUMEN

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. In late-stage AMD, geographic atrophy (GA) of dry AMD or choroidal neovascularization (CNV) of neovascular AMD eventually results in macular atrophy (MA), leading to significant visual loss. Despite the development of innovative therapies, there are currently no established effective treatments for MA. As a result, early detection of MA is critical in identifying later central macular involvement throughout time. Accurate and early diagnosis is achieved through a combination of clinical examination and imaging techniques. Our review of the literature depicts advances in retinal imaging to identify biomarkers of progression and risk factors for late AMD. Imaging methods like fundus photography; dye-based angiography; fundus autofluorescence (FAF); near-infrared reflectance (NIR); optical coherence tomography (OCT); and optical coherence tomography angiography (OCTA) can be used to detect and monitor the progression of retinal atrophy. These evolving diverse imaging modalities optimize detection of pathologic anatomy and measurement of visual function; they may also contribute to the understanding of underlying mechanistic pathways, particularly the underlying MA changes in late AMD.

RESUMEN

We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and that most of these TP53 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in NrasG12D/+ p53-/- (NP-/-) mice, NrasG12D/+ p53R172H/+ (NPmut) mice rapidly developed inflammation-associated AML. Under the inflammatory conditions, NPmut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and mostly normal cell proliferation despite MEK/ERK hyperactivation. RNA-Seq analysis revealed that oncogenic NRAS signaling and mutant p53 synergized to establish an NPmut-AML transcriptome distinct from that of NP-/- cells. The NPmut-AML transcriptome showed GATA2 downregulation and elevated the expression of inflammatory genes, including those linked to NF-κB signaling. NF-κB was also upregulated in human NRAS TP53 AML. Exogenous expression of GATA2 in human NPmut KY821 AML cells downregulated inflammatory gene expression. Mouse and human NPmut AML cells were sensitive to MEK and NF-κB inhibition in vitro. The proteasome inhibitor bortezomib stabilized the NF-κB-inhibitory protein IκBα, reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NPmut mice. Our study demonstrates that a p53 structural mutant synergized with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss.

Asunto(s)

Leucemia Mieloide Aguda , FN-kappa B , Proteína p53 Supresora de Tumor , Animales , Humanos , Ratones , Mutación con Ganancia de Función , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos , Mutación , FN-kappa B/metabolismo , Proteína p53 Supresora de Tumor/genética

Asunto(s)

COVID-19 , Humanos , Pandemias

RESUMEN

Early growth response gene (EGR1) is a transcription factor known to be a downstream effector of B-cell receptor signaling and Janus kinase 1 (JAK1) signaling in diffuse large B-cell lymphoma (DLBCL). While EGR1 is characterized as a tumor suppressor in leukemia and multiple myeloma, the role of EGR1 in lymphoma is unknown. Here we demonstrate that EGR1 is a potential oncogene that promotes cell proliferation in DLBCL. IHC analysis revealed that EGR1 expression is elevated in DLBCL compared with normal lymphoid tissues and the level of EGR1 expression is higher in activated B cell-like subtype (ABC) than germinal center B cell-like subtype (GCB). EGR1 expression is required for the survival and proliferation of DLBCL cells. Genomic analyses demonstrated that EGR1 upregulates expression of MYC and E2F pathway genes through the CBP/p300/H3K27ac/BRD4 axis while repressing expression of the type I IFN pathway genes by interaction with the corepressor NAB2. Genetic and pharmacologic inhibition of EGR1 synergizes with the BRD4 inhibitor JQ1 or the type I IFN inducer lenalidomide in growth inhibition of ABC DLBCL both in cell cultures and xenograft mouse models. Therefore, targeting oncogenic EGR1 signaling represents a potential new targeted therapeutic strategy in DLBCL, especially for the more aggressive ABC DLBCL. IMPLICATIONS: The study characterizes EGR1 as a potential oncogene that promotes cell proliferation and defines EGR1 as a new molecular target in DLBCL, the most common non-Hodgkin lymphoma.

Asunto(s)

Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Linfoma de Células B Grandes Difuso/genética , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Transducción de Señal/genética , Regulación hacia Arriba/genética

RESUMEN

B-cell lymphomas with atypical presentation or immunophenotype pose diagnostic challenges. Conventional ancillary tests (cytogenetics, FISH) can help, but have technical limitations. New technologies such as mate-pair sequencing (MPSeq) offer a route around these technical limitations.

RESUMEN

INTRODUCTION: Early reports have raised concerns regarding the clinical sensitivity of nasopharyngeal SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) testing for patients with COVID-19 symptoms, which has led to requests for repeat testing at our institution. However, to our knowledge, there are no reports to date of the utilization or results of repeat testing to help guide this practice. METHODS: The authors searched the institutional laboratory information system for consecutive patients who were tested for SARS-CoV-2 by RT-PCR of a nasopharyngeal specimen over a 1-month period. Characteristics and results of patients who received a single or multiple tests were documented and analyzed. RESULTS: Six thousand three (6003) tests were performed on 5757 patients; 272 (4.7%) patients were positive based on their initial test results. Two hundred thirty-six (4%) patients were tested more than once, with 226 (96%) tested twice. The largest proportion of these patients (n=160, 71%) were those who had an initial negative test followed by a repeat test for persistent symptoms. This group included all 7 patients who had discordant positive results on their second test; the result concordance rate within this group was 96%. CONCLUSION: In a population of patients with a low positive rate for SARS-CoV-2 by nasopharyngeal RT-PCR testing, repeat nasopharyngeal testing of negative patients who have persistent symptoms still yields a negative result in 96% of the cases.

Asunto(s)

Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/epidemiología , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus , COVID-19 , Prueba de COVID-19 , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Pandemias , Prevalencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , SARS-CoV-2 , Sensibilidad y Especificidad , Wisconsin/epidemiología

RESUMEN

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

Asunto(s)

Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide de Fase Crónica , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Oncología Médica , Cromosoma Filadelfia , Translocación Genética

RESUMEN

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited nonmalignant lymphoproliferative disorder characterized by heterozygous mutations within the first apoptosis signal receptor (FAS) signaling pathway. Defects in FAS-mediated apoptosis cause an expansion and accumulation of autoreactive CD4- and CD8- (double-negative) T cells, leading to cytopenias, splenomegaly, lymphadenopathy, autoimmune disorders, and a greatly increased lifetime risk of lymphoma. The differential diagnosis of ALPS includes infection, other inherited immunodeficiency disorders, primary and secondary autoimmune syndromes, and lymphoma. The most consistent pathologic feature is a florid paracortical expansion of double-negative T cells in lymph nodes. A presumptive clinical diagnosis can be made from symptoms and a constellation of laboratory test results. However, a definitive diagnosis requires ancillary testing and enables disease subclassification. Recognition of ALPS is critical, as treatment with immunosuppressive therapies can effectively reduce or ameliorate symptoms for most patients.

Asunto(s)

Síndrome Linfoproliferativo Autoinmune/diagnóstico , Ganglios Linfáticos/patología , Linfocitos T/patología , Apoptosis/fisiología , Síndrome Linfoproliferativo Autoinmune/metabolismo , Síndrome Linfoproliferativo Autoinmune/patología , Humanos , Transducción de Señal/fisiología

RESUMEN

Metabolic flexibility allows cells to adapt to various environments and limits the efficacy of metabolic drugs. Therapeutic targeting of cancer metabolism relies on defining limiting requirements and vulnerabilities in the highly dynamic metabolic network. Here, we characterize the metabolic reprogramming and identify cancer-specific metabolic vulnerabilities in response to the pharmacological inhibition of mitochondrial complex I. Our work reveals the adaptation mechanism in malignant lymphocytes providing resistance against the biguanides phenformin and metformin by transcriptionally reprogramming glucose metabolism. Metabolic adaptation to complex I inhibition is mediated by mitochondrial reactive oxygen species (mROS) serving as a mitochondrial stress signal activating hypoxia-inducible factor-1a (HIF-1a). Inhibition of the mROS/HIF-1a axis through antioxidants or direct suppression of HIF-1a selectively disrupts metabolic adaptation and survival during complex I dysfunction in malignant lymphocytes. Our results identify HIF-1a signaling as a critical factor in resistance against biguanide-induced mitochondrial dysfunction, allowing selective targeting of metabolic pathways in leukemia and lymphoma.

Asunto(s)

Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Linfocitos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Adolescente , Adulto , Anciano , Animales , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Metabolismo de los Hidratos de Carbono/fisiología , Hipoxia de la Célula/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Complejo I de Transporte de Electrón/metabolismo , Femenino , Humanos , Células Jurkat , Linfocitos/efectos de los fármacos , Masculino , Metformina/farmacología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Adulto Joven

RESUMEN

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma. Numerous studies have demonstrated many genetic aberrations in MCL in addition to the characteristic t(11:14), including frequent biallelic deletions of Bim, a proapoptotic member of the BCL-2 family. In mice, Bim deletion coupled with cyclin D1 overexpression generates pathologic and molecular features of human MCL. Since the regulation of apoptosis is crucial in MCL pathogenesis, we hypothesize that BIM expression may be associated with tumor cell survival. Clinical data and tissue from 100 nodal MCL cases between 1988 and 2009 were collected from three large academic medical centers. The average patient age of our MCL cohort was 65.5 years old (range, 42-97) with a 2:1 male to female ratio. Immunohistochemistry was performed with a validated anti-BIM antibody. Patients were separated into low and high BIM-expressing categories with a cutoff of 80%. As expected for a proapoptotic tumor suppressor, patients with high BIM expression were less likely to have progressive disease and more likely to have a complete response (P = .022). In addition, high BIM-expressing MCL tumors revealed a trend toward increased overall survival with this trend persisting in sub-analysis of Ann Arbor stages III and IV. No correlation between BIM expression, Ki-67 index, and MIPI score was observed, suggesting a role for BIM as a novel independent prognostic factor. While BIM is only one member of a complex family of apoptosis-regulating proteins, these findings may yield clinically relevant information for the prognosis and therapeutic susceptibility of MCL.

Asunto(s)

Proteína 11 Similar a Bcl2/metabolismo , Linfoma de Células B/patología , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/patología , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/fisiología , Ciclina D1/metabolismo , Femenino , Humanos , Inmunohistoquímica/métodos , Linfoma de Células B/genética , Linfoma de Células del Manto/genética , Masculino , Persona de Mediana Edad , Pronóstico , Translocación Genética

RESUMEN

PRMT5, which regulates gene expression by symmetric dimethylation of histones and non-histone target proteins, is overexpressed and plays a pathogenic role in many cancers. In diffuse large B cell lymphoma (DLBCL), the mechanisms of PRMT5 dysregulation and its role in lymphomagenesis remain largely unknown. Here we demonstrate that B cell receptor (BCR) signaling regulates PRMT5 expression in DLBCL cells. Immunohistochemical analysis reveals elevated levels of PRMT5 expression in DLBCL cases and in germinal center (GC) B cells when compared to naive B cells. PRMT5 can be induced in naive B cells by BCR stimulation. We discovered that BTK-NF-κB signaling induces PRMT5 transcription in activated B cell-like (ABC) DLBCL cells while BCR downstream PI3K-AKT-MYC signaling upregulates PRMT5 expression in both ABC and GCB DLBCL cells. PRMT5 inhibition inhibits the growth of DLBCL cells in vitro and patient derived xenografts. Genomic and biochemical analysis demonstrate that PRMT5 promotes cell cycle progression and activates PI3K-AKT signaling, suggesting a feedback regulatory mechanism to enhance cell survival and proliferation. Co-targeting PRMT5 and AKT by their specific inhibitors is lethal to DLBCL cell lines and primary cancer cells. Therefore, this study provides a mechanistic rationale for clinical trials to evaluate PRMT5 and AKT inhibitors for DLBCL.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Antineoplásicos/farmacología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Centro Germinal/patología , Humanos , Inmunohistoquímica , Isoquinolinas/farmacología , Linfoma de Células B Grandes Difuso/patología , Modelos Biológicos , FN-kappa B/metabolismo , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pirimidinas/farmacología , Transducción de Señal

RESUMEN

BACKGROUND: Follicular lymphoma (FL) is a common form of non-Hodgkin lymphoma with a wide spectrum of presentation. While grade 1/2 FL is considered low grade and grade 3B FL is approached as an aggressive lymphoma, the management of grade 3A FL remains controversial. PATIENTS AND METHODS: We performed a retrospective, multicenter analysis of patients aged ≥ 18 years with advanced stage 3/4 grade 3A FL diagnosed between January 2006 and July 2016. Patients were stratified by frontline chemotherapy regimen: anthracycline based (ATC), bendamustine (BD), and cyclophosphamide, vincristine, and prednisone (CVP). A total of 103 patients were identified from 6 contributing centers: 65 patients received ATC chemotherapy, 30 BD, and 8 CVP. The primary outcome was time to progression (TTP). Secondary outcomes included progression-free survival, overall survival, complete response rates, large cell transformation, and impact of standardized maximum uptake value on positron emission tomography/computed tomography with outcomes. Patient characteristics were similar among the 3 treatment groups. RESULTS: For TTP at 24 months from initiation of treatment, 72% of ATC, 79% of BD, and 50% of CVP patients had not experienced disease progression (P = .01). Multivariate analysis demonstrated a TTP benefit for ATC compared to CVP (hazard ratio 3.22; 95% confidence interval, 1.26-8.25; P = .01) but no difference when compared to BD. Similar findings were seen with progression-free survival. While overall survival was similar among the 3 arms, there was a higher risk of large cell transformation following BD and CVP. Last, standardized maximum uptake value on positron emission tomography/computed tomography did not affect TTP when comparing BD- and ATC-treated patients. CONCLUSION: Although ATC was superior to CVP, clinical outcomes (TTP, progression-free survival, and overall survival) were similar compared to BD chemotherapy for patients with grade 3A FL.

Asunto(s)

Linfoma Folicular/tratamiento farmacológico , Femenino , Humanos , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos

RESUMEN

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Oncología Médica/normas , Inhibidores de Proteínas Quinasas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/aislamiento & purificación , Médula Ósea/patología , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/aislamiento & purificación , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Oncología Médica/métodos , Selección de Paciente , Cromosoma Filadelfia , Pronóstico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/normas , Reacción en Cadena en Tiempo Real de la Polimerasa/normas , Medición de Riesgo/métodos , Medición de Riesgo/normas , Sociedades Médicas/normas , Estados Unidos

RESUMEN

INTRODUCTION: VcR-CVAD was developed as an intermediate-intensity induction regimen with maintenance rituximab (MR) to improve remission durations after first-line therapy for mantle cell lymphoma (MCL) in older and younger patients with MCL. PATIENTS AND METHODS: Patients with previously untreated MCL received VcR-CVAD induction chemotherapy for 6 cycles (21-day cycles). Patients achieving at least a partial response received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary endpoints were overall and complete response (CR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. There was an even distribution of patients < 60 years and ≥ 60 years. Mantle cell lymphoma international prognostic index medium- or high-risk disease was present in 60%. The overall response rate observed was 90% (77% CR/unconfirmed CR). After a median follow-up of 7.8 years, the 6-year PFS and OS were 53% and 70%, respectively. There was no difference in 6-year PFS or OS between the younger (age < 60 years) and older (age ≥ 60 years) subgroups. In a univariate analysis, lactate dehydrogenase, when analyzed for interaction with age, had a significant effect on PFS outcomes at 6 years. There were no pretreatment variables determined to have a significant effect on OS outcomes at 6 years. CONCLUSIONS: Long-term outcomes with VcR-CVAD are comparable with more intensive inductions and consolidation approaches. MCL is biologically heterogeneous, and durable remission can be achieved with intermediate intensity therapy. MR appears to contribute to these excellent outcomes.

Asunto(s)

Antineoplásicos Inmunológicos/uso terapéutico , Quimioterapia de Inducción/métodos , Linfoma de Células del Manto/tratamiento farmacológico , Rituximab/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Femenino , Humanos , Linfoma de Células del Manto/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inducción de Remisión , Rituximab/farmacología , Wisconsin

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Linfoma de Células del Manto/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/antagonistas & inhibidores , Oncogenes/genética , Adenina/análogos & derivados , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Piperidinas , Pirazoles/farmacología , Pirimidinas/farmacología