RESUMEN
BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Ipilimumab/administración & dosificación , Nivolumab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Células Escamosas/mortalidad , Neoplasias Esofágicas/mortalidad , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Ipilimumab/efectos adversos , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , Supervivencia sin Progresión , Análisis de SupervivenciaRESUMEN
PURPOSE OF REVIEW: This review analyzes currently available commercial transcatheter aortic valve replacement (TAVR) valves as well as valves in investigational status and those in preclinical testing. The design features and clinical outcomes of the Edwards SAPIEN S3 and Medtronic Evolut PRO+ are described and compared with highlight clinical circumstances where one may be favoured over the other. RECENT FINDINGS: Multiple randomized and nonrandomized trials have compared commercial and investigational TAVR valves. The results of these are summarized and discussed within this review with a focus on how the SAPIEN S3 and Evolut PRO+ both compare to each other as well as various valves in different investigational stages. SUMMARY: TAVR is an innovative and ground-breaking technology that will forever have revolutionized the management of aortic stenosis. Though the technology and valves themselves have come a long way, further developments are necessary if we are to continue to expand its indications and achieve a safer perioperative experience with more durable valves.
Asunto(s)
Estenosis de la Válvula Aórtica , Prótesis Valvulares Cardíacas , Reemplazo de la Válvula Aórtica Transcatéter , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/cirugía , Humanos , Diseño de Prótesis , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: The aim of this study was to compare outcomes of transcatheter heart valve (THV) choice in patients with left ventricular (LV) systolic dysfunction. BACKGROUND: The management congestive heart failure with combined LV systolic dysfunction and severe aortic stenosis (AS) is challenging, yet transcatheter aortic valve replacement (TAVR) has emerged as a suitable treatment option in such patients. Head-to-head comparisons among the balloon-expandable (BEV) and self-expandable (SEV) THV remain limited in this subgroup of patients. METHODS: In this retrospective study, we included patients with severe AS with LV systolic dysfunction (LVEF ≤40%) who underwent TAVR at four high volume centers. Two thousand and twenty-eight consecutive patients were analyzed, of which 335 patients met inclusion criteria. One hundred fourty-six patients (43%) received a SEV, and 189 patients (57%) received a BEV. RESULTS: Baseline characteristics were similar except for a higher proportion of females in the SEV group. The primary composite endpoint of in-hospital mortality, moderate or greater paravalvular (PVL), stroke, conversion to open surgery, aortic valve reintervention, and/or need for permanent pacemaker (PPM) was no different among THV choice. There was more PVL in the SEV group, but higher transaortic gradients in the BEV group. Clinical outcomes and quality of life measures were similar up to 1 year follow-up. CONCLUSION: The choice of THV in patients with severe AS and systolic dysfunction must be weighed on a case-by-case basis.
Asunto(s)
Estenosis de la Válvula Aórtica , Prótesis Valvulares Cardíacas , Reemplazo de la Válvula Aórtica Transcatéter , Disfunción Ventricular Izquierda , Femenino , Humanos , Estudios Retrospectivos , Volumen Sistólico , Calidad de Vida , Factores de Riesgo , Estenosis de la Válvula Aórtica/complicaciones , Estenosis de la Válvula Aórtica/cirugía , Válvula Aórtica/cirugía , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Disfunción Ventricular Izquierda/etiología , Resultado del Tratamiento , Diseño de PrótesisRESUMEN
Post-endoscopic retrograde cholangiopancreatography stenting is a well-established treatment for benign as well as malignant biliary obstruction. The most frequently encountered complication is stent clogging. Stent migration (proximal or distal), on the other hand, is not very common. Proximal migration of a choledochal endoprosthesis into the gallbladder has not yet been reported in the literature.
RESUMEN
Tribulus terrestris is known to possess many pharmacological properties, most notably its anticancer activities, owing to its rich steroidal saponin contents. Even though many reports are available elucidating the anticancer potential of the herb, we, for the very first time have attempted to isolate and identified the active compound present in seed crude saponin extract and confers its in silico docking ability with various cellular targets proteins. High performance thin layer chromatography confirms the presence of active saponins in leaf and seed saponin extracts which were further fractionated by silica gel column chromatography. Fractions collected were assessed for cytotoxicity on human breast cancer cells. High resolution liquid chromatography and mass spectroscopy was employ to identify the active components present in fraction with highest cytotoxicity. Intriguingly, Nautigenin type of steriodal saponin was identified to present in the active fraction of seed extract (SF11) and the identified compound was further analyzed for its in silico docking interaction using PyRx AutodockVina. Docking studies revealed the high binding affinity of Nuatigenin at significant sites with apoptotic proteins Bcl-2, Bax, caspase-3, caspase-8, p53 and apoptosis inducing factor along with cell surface receptors estrogen receptor, projesterone receptor, epidermal growth factor receptor, and human epidermal growth factor receptor-2. Thus, the conclusions were drawn that saponin fraction of Tribulus terrestis possesses active compounds having anticancer property and specifically, Nuatigenin saponin can be considered as an important therapeutic drug for the breast cancer treatment.
Asunto(s)
Proteínas/química , Saponinas/química , Saponinas/farmacología , Tribulus/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada/métodos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Extractos Vegetales/análisis , Extractos Vegetales/química , Proteínas/metabolismo , Saponinas/análisis , Esteroides/química , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
Adipose-derived mesenchymal stem cells (ASCs) transplantation has shown great promise for treating various diseases; however, poor viability of transplanted ASCs because of oxidative stress has limited its therapeutic efficiency. Plant saponins are recently been reported to have antioxidant activity tested in various cancer cell lines. This study was designed to investigate the protective effects of Tribulus terrestris saponins (TTS) on the proliferation of ASCs. The cytotoxic activity of hydrogen peroxide (H2 O2 ) was determined by treating ASCs with 100, 200, 300, 400, and 500 µM H2 O2 for 2 hours. ASCs were treated with 6.25, 12.5, 25, 50, and 100 µg/mL concentrations of TTS for the proliferative experiment. To check the protective effect of TTS, experiments were designed in two ways. In one set, ASCs were pretreated with different concentrations of TTS for 2 hours and then apoptosis was induced by treating them with 400 µM H2 O2 for next 2 hours, while in other set, ASCs were first treated with 400 µM H2 O2 for 2 hours and subsequently with different concentrations of TTS for 24 hours. The vitality and proliferation potential of cells were detected by 3-(4,5-Dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The result of the current study shows that in response to stress-induced by H2 O2 at concentration of 400 µM, ASCs underwent growth arrest and cell viability was reduced to half while treatment with TTS before and after H2 O2 exposure significantly prevents premature apoptosis. The findings suggest that saponins may act as an effective protective agent against oxidative stress-induced ASCs apoptosis.
Asunto(s)
Tejido Adiposo/citología , Proliferación Celular/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Saponinas/farmacología , Tribulus/química , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Peróxido de Hidrógeno/farmacología , Células Madre Mesenquimatosas/citología , Oxidantes/farmacología , Fitoterapia/métodos , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Factores de TiempoRESUMEN
Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine A (CsA) is the first-line therapy for acquired aplastic anemia (AA) in those not suitable for bone marrow transplant. Horse ATG (hATG) is preferred for this purpose, but its use is often impeded by shortages and costs. Being a rare disease, there is limited data on this therapy. This study aimed to evaluate this therapy in a large cohort of AA patients from western India. We retrospectively analyzed AA patients who received an indigenous preparation of hATG along with CsA as first-line treatment, between 2012 and 2015, at our center and evaluated the response, survival, and occurrence of adverse events. The response was further assessed separately for adults and children. During the period, 91 AA patients (4 non-severe, 57 severe and 30 very severe) were treated with IST. At 2 years, 23.5% adults and 39.1% children showed complete response and an overall of 68.1% cases became transfusion independent. More than half of the patients developed febrile neutropenia while roughly one sixth of the patients developed gum hypertrophy and/or hypertension. Two patients had clonal evolution. Mortality rate was calculated to be 31%; most common causes of death were infection and intracranial hemorrhage. The results of the study substantiate the effectiveness of IST in AA, using an inexpensive indigenous preparation of hATG along with CsA.
Asunto(s)
Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/mortalidad , Suero Antilinfocítico/administración & dosificación , Ciclosporina/administración & dosificación , Terapia de Inmunosupresión , Adolescente , Adulto , Suero Antilinfocítico/efectos adversos , Neutropenia Febril Inducida por Quimioterapia/mortalidad , Niño , Ciclosporina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Hipertensión/inducido químicamente , Hipertensión/mortalidad , India , Infecciones/inducido químicamente , Infecciones/mortalidad , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/mortalidad , Masculino , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
OBJECTIVE: We sought to use a novel technique to measure the functional hemodynamics of peripheral arterial lesions during endovascular interventions. BACKGROUND: Functional hemodynamics has not been thoroughly evaluated during endovascular interventions. The aim of our study is to evaluate the feasibility and the potential benefits of pedal pressures measurements from tibio-pedal access. METHODS: We retrospectively reviewed 100 consecutive patients who underwent endovascular interventions via tibio-pedal artery access between October 3, 2018 and December 15, 2018. Baseline and postintervention pedal pressures from the pedal sheaths were measured. We also evaluated the pedal-brachial index (PBI) which is defined as the pedal sheath pressure divided by the simultaneously brachial cuff pressure. We compared baseline pedal pressures, postintervention pedal pressures, baseline PBI, postintervention PBI, % change of PBI ([postintervention PBI minus baseline PBI]/baseline PBI), and resting ankle-brachial index (ABI) versus baseline PBI in this cohort of patients. RESULTS: All 100 patients had successful tibio-pedal artery access. Baseline pedal pressure was 70 + 30 mmHg with post intervention pedal pressure of 133 + 27 mmHg (p < .001). Baseline PBI was 0.75 + 0.24 with post intervention PBI of 1.09 + 0.19 (p < .001). The correlation coefficient of resting ABI vs. baseline PBI was 0.55. The % change of PBI was 63.2 + 52.4%. There was significant improvement of postintervention PBI when compared to baseline PBI in the majority of patients. CONCLUSIONS: Obtaining pedal pressures and PBI from tibio-pedal access can be a feasible tool for endovascular interventions. This simple technique can provide us important functional hemodynamics information before and after peripheral revascularization.
Asunto(s)
Presión Arterial , Procedimientos Endovasculares , Pierna/irrigación sanguínea , Enfermedad Arterial Periférica/terapia , Arterias Tibiales/fisiopatología , Anciano , Índice Tobillo Braquial , Bases de Datos Factuales , Procedimientos Endovasculares/efectos adversos , Femenino , Humanos , Masculino , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/fisiopatología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
CLINICAL FEATURES: Giant cell myocarditis (GCM) is a rare and a rapidly progressive disorder with fatal outcomes such that patients often require heart transplantation. We present a case of recurrent GCM in a transplanted patient with a history of Crohn disease requiring a novel therapeutic approach. THERAPEUTIC CHALLENGE: After the orthotopic heart transplantation, GCM recurred on aggressive immunosuppression over the months, which included corticosteroids, basiliximab, tacrolimus, antithymocyte globulin, and rituximab. Although combination immunosuppressive therapy containing cyclosporine and 2-4 additional drugs including corticosteroids, azathioprine, mycophenolate mofetil, muromonab, gammaglobulin, or methotrexate have shown to prolong the transplant-free survival by keeping the disease under control, its role in preventing and treating recurrence posttransplantation is unclear. SOLUTION: We added sirolimus, a macrolide antibiotic, with properties of T- and B-lymphocyte proliferation inhibition on the above immunosuppressive treatment postrecurrence of GCM. After sirolimus initiation and continuation, the patient has remained disease free.
Asunto(s)
Rechazo de Injerto/tratamiento farmacológico , Trasplante de Corazón/efectos adversos , Inmunosupresores/uso terapéutico , Miocarditis/terapia , Sirolimus/uso terapéutico , Aloinjertos/citología , Aloinjertos/diagnóstico por imagen , Aloinjertos/inmunología , Quimioterapia Combinada/métodos , Ecocardiografía , Células Gigantes/inmunología , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/inmunología , Corazón/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Miocarditis/diagnóstico , Miocardio/citología , Miocardio/inmunología , Recurrencia , Resultado del TratamientoRESUMEN
BACKGROUND: Improved equipment and techniques have resulted in transition from surgical bypass to endovascular intervention to treat superficial femoral artery (SFA) chronic total occlusions (CTO). A change in access site to radial (TRA) or tibiopedal (TPA) artery for the treatment of these SFA CTO has been reported. The feasibility, efficacy and safety of these two access sites for treatment of SFA CTO have not been reported. METHODS: We performed an as treated analysis of 184 SFA CTO interventions in 161 patients from 01/2014 to 09/2016 using either primary TRA or TPA (operator discretion) at two institutions. Primary end point was 30 day major adverse event (MAE) - death, amputation or target vessel revascularization, secondary endpoint was success of procedure. RESULTS: Primary TRA was used in 46 patients with 47 CTO lesions .Primary TPA was used in 115 patients with 137 CTO lesions. Primary crossing success rate was higher with TRA compared to TPA (74% vs 54%, P = 0.01). Dual TRA-TPA was required in 72 prior uncrossed lesions resulting in a crossing and procedural success of 99% and 96% respectively. The overall crossing and procedural success rate using either of these approaches was 99% and 98% respectively. The 30 day MAE was 5% in TRA arm, 0% in TPA arm and 2% in dual TRA-TPA arm, P = 0.08. All access sites were patent, confirmed by ultrasound. CONCLUSION: The treatment of SFA CTO is feasible and safe using both TRA or TPA approach providing high success rates and no access site complications.
Asunto(s)
Cateterismo Periférico/métodos , Procedimientos Endovasculares , Arteria Femoral , Enfermedad Arterial Periférica/terapia , Arteria Radial , Arterias Tibiales , Anciano , Anciano de 80 o más Años , Amputación Quirúrgica , Cateterismo Periférico/efectos adversos , Cateterismo Periférico/mortalidad , Enfermedad Crónica , Constricción Patológica , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Estudios de Factibilidad , Femenino , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/fisiopatología , Humanos , Hungría , Recuperación del Miembro , Masculino , Persona de Mediana Edad , Ciudad de Nueva York , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/mortalidad , Enfermedad Arterial Periférica/fisiopatología , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Acute lymphoblastic leukemia (ALL) is the most common malignancy in pediatric patients, and it is characterized by the presence of malignant lymphoblasts within the bone marrow and peripheral blood. The treatment of ALL involves induction, consolidation, reinduction, and maintenance therapy. Consolidation therapy in ALL-Berlin-Frankfurt-Münster 90 protocol involves the use of high-dose methotrexate (HDMTX, 5 g/m2) over 24 h as continuous infusion. The adverse effects due to HDMTX include renal dysfunction in 2%-12% patients, which can lead to increased systemic MTX exposure, leading to further myelosuppression, mucositis, hepatotoxicity, skin toxicity, and, in severe cases, multiorgan failure. Dermatologic toxicity due to MTX includes morbilliform drug rash, photoreactivation, photoenhancement, and skin hyperpigmentation. Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) are rare and possibly fatal reaction which can occur with MTX. Here, we describe a patient with B-cell ALL who developed TEN after administration of HDMTX.
RESUMEN
BACKGROUND: To introduce the "uniform cortex sign" (UCS) and evaluate its performance as a diagnostic test for the presence of diffuse cortical injury (DCI). METHODS: The study was approved by our institutional review board. Three experienced neuroradiologists were given a tutorial on the UCS. They were subsequently presented with 14 cases (7 control patients and 7 DCI patients with the UCS) in random order and asked to determine whether the UCS was present. Each case consisted of selected DWI, T2-weighted, and FLAIR images from unenhanced 1.5T MRI examinations. A consensus result for each case was determined by unanimity or majority rule. RESULTS: All control patients were correctly identified as normal by all neuroradiologists (7/7). The UCS was correctly identified in 86% of DCI patients (6/7). UCS interrater agreement was high (multirater κ=0.81). CONCLUSIONS: This small study shows that the UCS can identify DCI, especially in patients with hypoxic-ischemic encephalopathy. The UCS can be subtle, hence the reader must be vigilant for this finding. The accuracy of the UCS may depend on the extent of cortical injury and time between injury and MRI. Also, a UCS may be reversible, as in our case of viral meningoencephalitis.
Asunto(s)
Lesiones Encefálicas/patología , Encéfalo/patología , Imagen de Difusión por Resonancia Magnética , Hipoxia-Isquemia Encefálica/patología , Adolescente , Adulto , Lesiones Encefálicas/diagnóstico , Niño , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Humanos , Hipoxia-Isquemia Encefálica/diagnóstico , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
PURPOSE: To evaluate the risk of and risk factors for retinal neovascularization (NV) in cases of uveitis. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with uveitis at 4 US academic ocular inflammation subspecialty practices. METHODS: Data were ascertained by standardized chart review. Prevalence data analysis used logistic regression. Incidence data analysis used survival analysis with time-updated covariates where appropriate. MAIN OUTCOME MEASURES: Prevalence and incidence of NV. RESULTS: Among uveitic eyes of 8931 patients presenting for initial evaluation, 106 of 13,810 eyes had NV (prevalence = 0.77%, 95% confidence interval [CI], 0.60-0.90). Eighty-eight more eyes developed NV over 26,465 eye-years (incidence, 0.33%/eye-year; 95% CI, 0.27-0.41). Factors associated with incident NV include age <35 years compared with >35 years (adjusted hazard ratio [aHR], 2.4; 95% CI, 1.5-3.9), current cigarette smoking (aHR, 1.9; 95% CI, 1.1-3.4), and systemic lupus erythematosus (aHR, 3.5, 95% CI, 1.1-11). Recent diagnosis of uveitis was associated with an increased incidence of NV (compared with patients diagnosed >5 years ago, aHR, 2.4 [95% CI, 1.1-5.0] and aHR, 2.6 [95% CI, 1.2-6.0] for diagnosis within <1 year vs. 1-5 years, respectively). Compared with anterior uveitis, intermediate uveitis (aHR, 3.1; 95% CI, 1.5-6.6), posterior uveitis (aHR, 5.2; 95% CI, 2.5-11), and panuveitis (aHR, 4.3; 95% CI, 2.0-9.3) were associated with a similar degree of increased NV incidence. Active (aHR, 2.1, 95% CI, 1.2-3.7) and slightly active (aHR, 2.4, 95% CI, 1.3-4.4) inflammation were associated with an increased incidence of NV compared with inactive inflammation. Neovascularization incidence also was increased with retinal vascular occlusions (aHR, 10, 95% CI, 3.0-33), retinal vascular sheathing (aHR, 2.6, 95% CI, 1.4-4.9), and exudative retinal detachment (aHR, 4.1, 95% CI, 1.3-13). Diabetes mellitus was associated with a somewhat increased incidence of retinal NV (aHR, 2.3, 95% CI, 1.1-4.9), and systemic hypertension (aHR 1.5, 95% CI, 0.89-2.4) was associated with nonsignificantly increased NV incidence. Results were similar in sensitivity analyses excluding the small minority of patients with diabetes mellitus. CONCLUSIONS: Retinal NV is a rare complication of uveitis, which occurs more frequently in younger patients, smokers, and those with intermediate/posterior/panuveitis, systemic vasculopathy, retinal vascular disease, or active inflammation. Inflammation and retinal NV likely are linked; additional studies are needed to further elucidate this connection.
Asunto(s)
Neovascularización Retiniana/epidemiología , Neovascularización Retiniana/etiología , Uveítis/complicaciones , Adulto , Estudios de Cohortes , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Prevalencia , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Transpedal access is increasingly utilized for peripheral vascular catheterization. There is a paucity of data on the use of radial hemostasis devices as an alternative to manual compression for achievement of hemostasis after this approach. OBJECTIVE: To compare safety and efficacy of two hemostasis devices following transpedal catheterization for lower extremity revascularization for peripheral arterial disease. METHODS: A consecutive cohort of patients with bilateral Rutherford 2-5 disease who underwent transpedal catheterization for peripheral vascular interventions were retrospectively analyzed. In each patient, retrograde tibial artery access was obtained, a 4 French sheath was placed, and all revascularization was performed via tibial access. In all patients, a TR Band™ (Terumo Medical, n = 215) and/or VasoStat™ (Forge Medical, n = 99) were used to apply puncture site compression, following removal of the tibial sheath until hemostasis was achieved. Safety and efficacy of each device was compared. RESULTS: Puncture site hemostasis was achieved in all patients within 2 hours of sheath removal facilitating early discharge. Two access site pseudoaneurysms occurred within 30 days of revascularization, one of which followed TR Band™ placement and the other following VasoStat™ placement (P = 0.53). Each patient was successfully treated with ultrasound-guided thrombin injection. Loss of access site patency by duplex ultrasound occurred in 2 patients following the TR Band™ and a single patient following the VasoStat™ (P = 1.0). CONCLUSION: Both the TR Band™ and the VasoStat™ were effective in achieving hemostasis following transpedal catheterization with low rates of complications.
Asunto(s)
Aneurisma Falso , Cateterismo Periférico , Hemostasis Quirúrgica , Técnicas Hemostáticas/instrumentación , Enfermedad Arterial Periférica , Complicaciones Posoperatorias , Arterias Tibiales/cirugía , Anciano , Aneurisma Falso/diagnóstico , Aneurisma Falso/etiología , Aneurisma Falso/prevención & control , Cateterismo Periférico/efectos adversos , Cateterismo Periférico/métodos , Investigación sobre la Eficacia Comparativa , Femenino , Hemostasis Quirúrgica/efectos adversos , Hemostasis Quirúrgica/instrumentación , Hemostasis Quirúrgica/métodos , Humanos , Extremidad Inferior/irrigación sanguínea , Masculino , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/cirugía , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/prevención & control , Resultado del TratamientoRESUMEN
PURPOSE: Oral administration of anticancer agents presents a series of advantages for patients. However, most of the anticancer drugs have poor water solubility leading to low bioavailability. METHODS: Controlled released spray dried matrix system of Gefitinib with hydroxypropyl ß-cyclodextrin, chitosan, hydroxy propyl methyl cellulose, vitamin E TPGS, succinic acid were used for the design of formulations to improve the oral absorption of Gefitinib. Spray drying with a customized spray gun which allows simultaneous/pulsatile flow of two different liquid systems through single nozzle was used to prepare Gefitinib spray dried formulations (Gef-SD). Formulation was characterized by in vitro drug release and Caco-2 permeability studies. Pharmacokinetic studies were performed in Sprague Dawley rats. Efficacy of Gef-SD was carried out in A431 xenografts models in nude mice. RESULTS: In Gef-SD group 9.14-fold increase in the AUC was observed compared to free Gef. Improved pharmacokinetic profile of Gef-SD translated into increase (1.75 fold compared to Gef free drug) in anticancer effects. Animal survival was significantly increased in Gef formulation treated groups, with superior reduction in the tumor size (1.48-fold) and volumes (1.75-fold) and also increase in the anticancer effects (TUNEL positive apoptotic cells) was observed in Gef-SD treated groups. Further, western blot, immunohistochemical and proteomics analysis demonstrated the increased pharmacodynamic effects of Gef-SD formulations in A431 xenograft tumor models. CONCLUSION: Our studies suggested that Gefitinib can be successfully incorporated into control release microparticles based oral formulation with enhanced pharmacokinetic and pharmacodynamic activity. This study demonstrates the novel application of Gef in A431 tumor models.
Asunto(s)
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Quinazolinas/farmacocinética , Quinazolinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Área Bajo la Curva , Disponibilidad Biológica , Células CACO-2 , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Química Farmacéutica , Excipientes , Gefitinib , Humanos , Ratones Desnudos , Proteómica , Quinazolinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Neoplasias Cutáneas/genética , Solubilidad , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Breast cancer is the leading cause of malignancies among women globally. The triple negative breast cancer (TNBC) subtype is the most difficult to treat and accounts for 15% of all cases. Targeted therapies have been developed for TNBC but come short of clinical translation due to acquired tumor resistance. An effective therapy against TNBC must combine properties of target specificity, efficient tumor killing, and translational relevance. The objective of this study was to formulate a nontoxic, cationic, lipid-conjugated estrogenic derivative (ESC8), with demonstrated anticancer activity, for oral delivery in mice bearing triple negative breast cancer (TNBC) as xenograft tumors. The in vitro cell viability, Caco-2 permeability, and cell cycle dynamics of ESC8-treated TNBC cells were investigated. ESC8 was formulated as liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) and characterized for size, zeta potential, entrapment efficiency, size stability, and tumor biodistribution. Pharmacokinetic modeling of plasma concentration-time course data was carried out following intravenous and oral administration in Sprague-Dawley rats. In vivo efficacy investigation of ESC8-SLNC was carried out in Nu/Nu mice bearing MDA-MB-231 TNBC as xenograft tumors, and the molecular dynamics modulating tumor growth inhibition was analyzed by Western blot. In vitro ESC8 inhibited TNBC and non-TNBC cell viability with IC50 ranging from 1.81 to 3.33 µM. ESC8 was superior to tamoxifen and Cisplatin in inhibiting MDA-MB-231 cell viability; and at 2.0 µM ESC8 enhanced Cisplatin cytotoxicity 16-fold. Intravenous ESC8 (2.0 mg/kg) was eliminated at a rate of 0.048 ± 0.01 h(-1) with a half-life of 14.63 ± 2.95 h in rats. ESC8 was orally bioavailable (47.03%) as solid lipid nanoparticles (ESC8-SLN). ESC8-SLN (10 mg/kg/day, ×14 days, p.o.) inhibited breast tumor growth by 74% (P < 0.0001 vs control) in mice bearing MDA-MB-231 cells as xenografts; and when given in combination with Cisplatin (2.0 mg/kg/biweekly, ×2 weeks, IV), tumor growth was inhibited by 87% (P = 0.0002, vs ESC8-SLN; 10 mg/kg/day, ×14 days, p.o). ESC8-SLN tumor growth inhibition was associated with increased expression of p21 and Caspase-9; as well as by inhibition of EGFR, Slug, p-Akt1, Vimentin, NFkß, and IKKγ. These results show the promise of ESC8 as an oral adjuvant or neoadjuvant against triple negative breast cancer.
Asunto(s)
Cisplatino/administración & dosificación , Portadores de Fármacos , Estrógenos/análogos & derivados , Lípidos/química , Nanopartículas/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Células CACO-2 , Ciclo Celular , Línea Celular Tumoral , Separación Celular , Supervivencia Celular , Sinergismo Farmacológico , Estradiol/química , Femenino , Citometría de Flujo , Humanos , Concentración 50 Inhibidora , Liposomas/química , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Tamaño de la Partícula , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE: To compare success rates of a guidewire and microcatheter strategy vs the use of specialized crossing devices to traverse infrainguinal peripheral artery chronic total occlusions (CTOs). METHODS: For this analysis, data on 438 consecutive infrainguinal CTO interventions in 438 patients (mean age 63.2 years; 402 men) performed between August 2006 and May 2014 were extracted from the multicenter Excellence in Peripheral Artery Disease (XLPAD) database (ClinicalTrials.gov; identifier NCT01904851). Primary technical success constituted placement of a guidewire in the true lumen, past the distal CTO cap, with the initial crossing strategy. RESULTS: A wire-catheter strategy was used in 295 (67.4%) and a specialized CTO crossing device in 143 (32.6%) patients (p<0.001). Primary crossing technical success was higher with CTO devices (72.1% vs 51.9%, p<0.001). The primary wire-catheter arm used significantly more secondary CTO devices (28.1% vs 17.5%) and/or provisional re-entry devices (26.7% vs 4.9%) compared with the primary CTO device arm (both p<0.001). Secondary crossing technical success (defined as crossing with an alternate strategy: 67.5% vs 71.4%, p=1.000), provisional crossing technical success (defined as use of a re-entry device: 84.2% vs 87.5%, p=0.768), and procedure success (93.6% vs 90.9%, p=0.332) were similar between the wire-catheter and CTO device strategies, respectively. No differences were observed in periprocedural complications or 30-day adverse events; however, at 12 months, there was a significantly higher surgical revascularization rate in the primary wire-catheter arm (8.8% vs 2.8%, p=0.025). CONCLUSION: Infrainguinal peripheral artery CTO crossing is frequently attempted with a wire-catheter technique; however, an initial CTO crossing device approach is associated with higher primary technical success. Overall procedure success is similar with both strategies.
Asunto(s)
Arteriopatías Oclusivas/cirugía , Pierna/irrigación sanguínea , Enfermedades Vasculares Periféricas/cirugía , Dispositivos de Acceso Vascular , Angiografía , Anticoagulantes/administración & dosificación , Cateterismo , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
PURPOSE: In an effort to prepare an oral dosage form for poorly bioavailable anti-cancer agents, we have incorporated spray drying using a customized spray gun generating enteric coated Self-emulsifying drug delivery systems. The objective of this study was to design and evaluate pharmacokinetics and pharmacodynamic characteristics of Spray BIO-Max DIM-P (SB DIM-P). METHODS: SB DIM-P was prepared and optimized based on physico-chemical characteristics using design of experiment (DOE-Vr 8.0) software. Pharmacokinetic parameters in dogs and rats were evaluated and analyzed using Winonlin. Anti-tumor activity was carried out in orthotopic and metastatic lung tumor models using size M capsules in mice. RESULTS: Based on the optimization using DOE analysis of SB DIM-P characteristics, formulations were selected for further investigation. Pharmacokinetic studies showed a 30% increase in oral bioavailability in rats and ~2.9 times more bioavailability of SB DIM-P compare to solution in dogs. SB DIM-P showed ~20-25% more tumor volume/weight reduction in H1650 metastatic tumor model and ~25-30% tumor volume/weight reduction in A549 orthotopic tumor model compared to DIM-P solution. CONCLUSIONS: Our studies demonstrate the potential application of spray dried enteric coated self-emulsifying delivery system (SB DIM-P) to enhances oral absorption and efficacy of DIM-P in lung tumor models.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacocinética , Indoles/química , Indoles/farmacocinética , Neoplasias Pulmonares/tratamiento farmacológico , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Disponibilidad Biológica , Línea Celular Tumoral , Química Farmacéutica , Perros , Emulsiones , Humanos , Indoles/administración & dosificación , Indoles/uso terapéutico , Inyecciones Intravenosas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones Desnudos , Metástasis de la Neoplasia , Ratas Sprague-Dawley , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Epidemiologic and clinical research suggests important gender-related differences in the prevalence, presentation, associated conventional and non-conventional risk factors, management and outcomes of coronary heart disease (CHD) patients. Adequate data is not available for Indian population where prevalence of CHD and depression is high. METHOD: We conducted an observational, single-center, study from January 2010 to December 2011 on 10450 consecutive patients visiting a tertiary care center, Ahmedabad, Gujarat, India who presented with complaints related to CHD. RESULTS: Of these, 6867 patients had coronary artery disease (CAD) as confirmed by angiographic investigation; 5678 were males, and 1189 were females with similar mean age. As compared to males, females had higher prevalence of hypertension, diabetes and obesity while males had higher prevalence of smoking. Invasive treatment options like Coronary Artery Bypass Grafting (p < 0.001) and Percutaneous Coronary Intervention (p = 0.001) were used less often to treat females, and medical therapy (p < 0.001) was the preferred treatment option irrespective of the contributing risk factors/extent of CAD. Depression was observed in 39.8% of acute coronary syndrome patients (n = 1648) as assessed by MARDS scale. It was higher in female patients and in low socioeconomic strata (p < 0.001).At 12 and 36 months, rates of revascularization (p < 0.001) and mortality (p < 0.005) were higher with poor quality of life (QoL) (P < 0.001) in depressed CAD patients. CONCLUSION: In India, women appear to have a higher prevalence of hypertension, diabetes, obesity, and family history of CHD. Yet women get invasive treatments less often than men. Depression is also more common in women and is associated with poor QoL and early mortality than men.
Asunto(s)
Enfermedad de la Arteria Coronaria , Adulto , Anciano , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/terapia , Depresión/diagnóstico , Depresión/epidemiología , Femenino , Humanos , India/epidemiología , Masculino , Persona de Mediana Edad , Calidad de Vida , Factores de RiesgoRESUMEN
PURPOSE: Evaluation of tumor targeting pegylated EphA2 peptide coated nanoparticles (ENDDs) of a novel anticancer agent DIM-C-pPhC6H5 (DIM-P) and Docetaxel (DOC) and investigate its antitumor activity and potential for treatment of lung cancer. METHODS: Nanoparticles were prepared with DIM-P and DOC (NDDs) using Nano-DeBEE. ENDDs were prepared by conjugating NDDs with 6His-PEG2K-EphA2 peptide and characterized for physicochemical properties, binding assay, cytotoxicity, cellular uptake studies, drug release and pharmacokinetic parameters. Anti-tumor activity of ENDDs was evaluated using a metastatic H1650 and orthotopic A549 tumor models in nude mice and tumor tissue were analyzed by RT-PCR and immunohistochemistry. RESULTS: Particle size and entrapment efficiency of ENDDs were 197 ± 21 nm and 95 ± 2%. ENDDs showed 32.5 ± 3.5% more cellular uptake than NDDs in tumor cells. ENDDs showed 23 ± 3% and 26 ± 4% more tumor reduction compared to NDDs in metastatic and orthotopic tumor models, respectively. In-vivo imaging studies using the Care stream MX FX Pro system showed (p < 0.001) 40-60 fold higher flux for ENDDs compared to NDDs at tumor site. CONCLUSIONS: The results emanating from these studies demonstrate anti-cancer potential of DIM-P and the role of ENDDs as effective tumor targeting drug delivery systems for lung cancer treatment.