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1.
J Am Heart Assoc ; : e021406, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34632807

RESUMO

Background Factors associated with poor prognosis following receipt of extracorporeal membrane oxygenation (ECMO) in adults with cardiac arrest remain unclear. We aimed to identify predictors of mortality in adults with cardiac arrest receiving ECMO in a nationally representative sample. Methods and Results The US Healthcare Cost and Utilization Project's National Inpatient Sample was used to identify 782 adults hospitalized with cardiac arrest who received ECMO between 2006 and 2014. The primary outcome of interest was all-cause in-hospital mortality. Factors associated with mortality were analyzed using multivariable logistic regression. The overall in-hospital mortality rate was 60.4% (n=472). Patients who died were older and more often men, of non-White race, and with lower household income than those surviving to discharge. In the risk-adjusted analysis, independent predictors of mortality included older age, male sex, lower annual income, absence of ventricular arrhythmia, absence of percutaneous coronary intervention, and presence of therapeutic hypothermia. Conclusions Demographic and therapeutic factors are independently associated with mortality in patients with cardiac arrest receiving ECMO. Identification of which patients with cardiac arrest may receive the utmost benefit from ECMO may aid with decision-making regarding its implementation. Larger-scale studies are warranted to assess the appropriate candidates for ECMO in cardiac arrest.

2.
Ann Thorac Surg ; 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34437853

RESUMO

BACKGROUND: Variation in degenerative mitral morphology may contribute to suboptimal repair rates. This study evaluates outcomes of a standardized mitral repair technique. METHODS: An institutional clinical registry was used to identify 1036 consecutive patients undergoing robotic mitral surgery between 2005-2020: 87% (n=902) had degenerative disease. Calcification, failed transcatheter repair, and endocarditis were excluded, leaving 582 (68%) patients with isolated posterior leaflet and 268 (32%) with anterior/bileaflet prolapse. Standardized repair comprised triangular resection and true-sized flexible band in posterior leaflet prolapse. Freedom from >2+ moderate mitral regurgitation stratified by prolapse location was assessed using competing risk analysis with death as a competing event. Median follow-up was 5.5 (range 0-15) years. RESULTS: Of patients with isolated posterior leaflet prolapse, 87% (n=506) had standardized repairs, and 13% (n=76) had additional or non-resectional techniques, versus 24% (n=65) and 76% (n=203) respectively for anterior/bileaflet prolapse (P<0.001). Adjunctive techniques in the isolated posterior leaflet group included chordal reconstruction (8.6%, n=50) and commissural sutures (3.4%, n=20). Overall, median clamp time was 80 (IQR 68-98) minutes, 17 patients required intra-operative re-repair, and 6 required mitral replacement. Freedom from >2+ regurgitation or reintervention at 10 years was 92% for posterior prolapse (versus 83% for anterior/bileaflet prolapse). Anterior/bileaflet prolapse was associated with late >2+ regurgitation (HR 3.0, 95% CI 1.3-7.0). CONCLUSIONS: Posterior leaflet prolapse may be repaired in > 99% of patients using triangular resection and band annuloplasty, with satisfactory long-term durability. Increased risk of complex repairs and inferior durability highlights the value of identifying anterior and bileaflet prolapse pre-operatively.

3.
Ann Thorac Surg ; 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34197828

RESUMO

Mitral valve repair is infrequently performed in patients undergoing corrective surgery for failed mitral transcatheter edge-to-edge repair (TEER) in current US practice. This article describes surgical techniques for reconstructive surgery following failed TEER. A total of nine patients underwent robotic-assisted mitral surgery following failed TEER between 2010 and 2020 at a single center. Repair was completed in 88.9% (n=8) patients and freedom from >2+ mitral regurgitation was 87.5% (n=7) at a median follow up of 1.9 years.

4.
J Am Coll Cardiol ; 78(1): 1-9, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-33945832

RESUMO

BACKGROUND: Transcatheter edge-to-edge (TEER) mitral repair may be complicated by residual or recurrent mitral regurgitation. An increasing need for surgical reintervention has been reported, but operative outcomes are ill defined. OBJECTIVES: This study evaluated national outcomes of mitral surgery after TEER. METHODS: The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database was used to identify 524 adults who underwent mitral surgery after TEER between July 2014 and June 2020. Emergencies (5.0%; n = 26), previous mitral surgery (5.3%; n = 28), or open implantation of transcatheter prostheses (1.5%; n = 8) were excluded. The primary outcome was 30-day or in-hospital mortality. RESULTS: In the study cohort of 463 patients, the median age was 76 years (interquartile range [IQR]: 67 to 81 years), median left ventricular ejection fraction was 57% (IQR: 48% to 62%), and 177 (38.2%) patients had degenerative disease. Major concomitant cardiac surgery was performed in 137 (29.4%) patients: in patients undergoing isolated mitral surgery, the median STS-predicted mortality was 6.5% (IQR: 3.9% to 10.5%), the observed mortality was 10.2% (n = 23 of 225), and the ratio of observed to expected mortality was 1.2 (95% confidence interval [CI]: 0.8 to 1.9). Predictors of mortality included urgent surgery (odds ratio [OR]: 2.4; 95% CI: 1.3 to 4.6), nondegenerative/unknown etiology (OR: 2.2; 95% CI: 1.1 to 4.5), creatinine of >2.0 mg/dl (OR: 3.8; 95% CI: 1.9 to 7.9) and age of >80 years (OR: 2.1; 95% CI: 1.1 to 4.4). In a volume outcomes analysis in an expanded cohort of 591 patients at 227 hospitals, operative mortality was 2.6% (n = 2 of 76) in 4 centers that performed >10 cases versus 12.4% (n = 64 of 515) in centers performing fewer (p = 0.01). The surgical repair rate after failed TEER was 4.8% (n = 22) and was 6.8% (n = 12) in degenerative disease. CONCLUSIONS: This study indicates that mitral repair is infrequently achieved after failed TEER, which may have implications for treatment choice in lower-risk and younger patients with degenerative disease. These findings should inform patient consent for TEER, clinical trial design, and clinical performance measures.


Assuntos
Cateterismo Cardíaco , Implante de Prótese de Valva Cardíaca , Anuloplastia da Valva Mitral/efeitos adversos , Insuficiência da Valva Mitral , Valva Mitral , Complicações Pós-Operatórias , Reoperação , Fatores Etários , Idoso , Cateterismo Cardíaco/efeitos adversos , Cateterismo Cardíaco/métodos , Feminino , Doenças das Valvas Cardíacas/patologia , Doenças das Valvas Cardíacas/cirurgia , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/métodos , Mortalidade Hospitalar , Humanos , Masculino , Valva Mitral/diagnóstico por imagem , Valva Mitral/patologia , Valva Mitral/cirurgia , Anuloplastia da Valva Mitral/métodos , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/mortalidade , Insuficiência da Valva Mitral/cirurgia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/cirurgia , Prognóstico , Recidiva , Reoperação/efeitos adversos , Reoperação/métodos , Reoperação/estatística & dados numéricos , Fatores de Risco , Estados Unidos
5.
Orthop J Sports Med ; 7(4): 2325967119838251, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31019985

RESUMO

Background: Injury to the posterolateral corner (PLC) of the knee requires reconstruction to restore coronal and rotary stability. Two commonly used procedures are the Arciero reconstruction technique (ART) and the LaPrade reconstruction technique (LRT). To the authors' knowledge, these techniques have not been biomechanically compared against one another. Purpose: To identify if one of these reconstruction techniques better restores stability to a PLC-deficient knee and if concomitant injury to the proximal tibiofibular joint or anterior cruciate ligament affects these results. Study Design: Controlled laboratory study. Methods: Eight matched-paired cadaveric specimens from the midfemur to toes were used. Each specimen was tested in 4 phases: intact PLC (phase 1), PLC sectioned (phase 2), PLC reconstructed (ART or LRT) (phase 3), and tibiofibular (phase 4A) or anterior cruciate ligament (phase 4B) sectioning with PLC reconstructed. Varus angulation and external rotation at 0º, 20º, 30º, 60º, and 90º of knee flexion were quantified at each phase. Results: In phase 3, both reconstructions were effective at restoring laxity back to the intact state. However, in phase 4A, both reconstructions were ineffective at stabilizing the joint owing to tibiofibular instability. In phase 4B, both reconstructions had the potential to restrict varus angulation motion. There were no statistically significant differences found between reconstruction techniques for varus angulation or external rotation at any degree of flexion in phase 3 or 4. Conclusion: The LRT and ART are equally effective at restoring stability to knees with PLC injuries. Neither reconstruction technique fully restores stability to knees with combined PLC and proximal tibiofibular joint injuries. Clinical Relevance: Given these findings, surgeons may select their reconstruction technique based on their experience and training and the specific needs of their patients.

6.
Cancer ; 122(6): 875-83, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26709987

RESUMO

BACKGROUND: The type 3 Dearing reovirus (Reolysin) is a naturally occurring virus that preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. It induces host immunity and cell cycle arrest and acts synergistically with cytotoxic agents. METHODS: This study evaluated Reolysin combined with paclitaxel and carboplatin in patients with metastatic/recurrent KRAS-mutated or epidermal growth factor receptor (EGFR)-mutated/amplified non-small cell lung cancer. RESULTS: Thirty-seven patients were treated. Molecular alterations included 20 KRAS mutations, 10 EGFR amplifications, 3 EGFR mutations, and 4 BRAF-V600E mutations. In total, 242 cycles (median, 4; range, 1-47) were completed. The initial doses were area under the curve (AUC) 6 mg/mL/min for carboplatin, 200 mg/m(2) for paclitaxel on day 1, and 3 × 10(10) 50% tissue culture infective dose for Reolysin on days 1 to 5 of each 21-day cycle. Because of diarrhea and febrile neutropenia (in the first 2 patients), subsequent doses were reduced to 175 mg/m(2) for paclitaxel and AUC 5 mg/mL/min for carboplatin. Toxicities included fatigue, diarrhea, nausea/vomiting, neutropenia, arthralgia/myalgia, anorexia, and electrolyte abnormalities. Response Evaluation Criteria in Solid Tumors 1.0 responses included the following: partial response for 11 patients, stable disease (SD) for 20 patients, progressive disease for 4 patients, and not evaluable for 2 patients (objective response rate, 31%; 90% 1-sided lower confidence interval, 21%). Four SD patients had >40% positron emission tomography standardized uptake value reductions. The median progression-free survival, median overall survival, and 12-month overall survival rate were 4 months, 13.1 months, and 57%, respectively. Seven patients were alive after a median follow-up of 34.2 months; they included 2 patients without disease progression at 37 and 50 months. CONCLUSIONS: Reolysin in combination with paclitaxel and carboplatin was well tolerated. The observed response rate suggests a benefit of the reovirus for chemotherapy. A follow-up randomized study is recommended. The proportion of patients surviving longer than 2 years (30%) suggests a second/third-line treatment effect or possibly the triggering of an immune response after tumor reovirus infiltration.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Orthoreovirus Mamífero 3 , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia Viral Oncolítica , Proteínas Proto-Oncogênicas p21(ras)/genética , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Terapia Viral Oncolítica/métodos
7.
BMC Cancer ; 15: 513, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-26156229

RESUMO

BACKGROUND: Activating mutations in RAS are present in the majority of pancreatic cancer cases and represent an ideal therapeutic target. Reolysin is a proprietary formulation of oncolytic reovirus that is currently being evaluated in multiple clinical trials due to its ability to selectively replicate in cells harboring an activated RAS pathway. Here we report for the first time the presence of reovirus replication and induction of endoplasmic reticular (ER) stress in a primary tumor specimen collected from a pancreatic cancer patient receiving intravenous Reolysin and gemcitabine. CASE PRESENTATION: We describe the case of a 54-year old patient diagnosed with pancreatic adenocarcinoma in February 2012. Analysis of a tumor biopsy revealed an activating KRAS mutation (G12D) and the patient was started on first-line treatment with Reolysin in combination with gemcitabine in March 2012. Stable disease was achieved with significant improvement in cancer-related pain. Following 25 cycles of treatment over 23 months, a second biopsy was collected and immunohistochemical analyses revealed the presence of reovirus replication and induction of the ER stress-related gene GRP78/BIP and the pro-apoptotic protein NOXA. Importantly, co-localization of reoviral protein and active caspase-3 was also observed in the biopsy specimen. CONCLUSION: This is the first report of reoviral protein detection in primary tumor biopsies taken from a pancreatic cancer patient receiving intravenous Reolysin therapy. The accumulation of reoviral protein was associated with ER stress induction and caspase-3 processing suggesting that Reolysin and gemcitabine treatment exhibited direct pro-apoptotic activity against the tumor.


Assuntos
Antineoplásicos , Desoxicitidina/análogos & derivados , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Reoviridae/genética , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Pâncreas/virologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/virologia , Proteínas Proto-Oncogênicas p21(ras) , Reoviridae/metabolismo
8.
Clin Cancer Res ; 21(6): 1305-12, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25424857

RESUMO

PURPOSE: Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide. EXPERIMENTAL DESIGN: In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25-1,000 mg/m(2) through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose. RESULTS: The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m(2) combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a predefined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14% of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus. CONCLUSIONS: Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies.


Assuntos
Ciclofosfamida/uso terapêutico , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Reoviridae/fisiologia , Adulto , Idoso , Anticorpos Neutralizantes/efeitos dos fármacos , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/efeitos dos fármacos , Anticorpos Antivirais/imunologia , Terapia Combinada , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia
9.
Mol Ther ; 22(5): 1056-62, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24553100

RESUMO

Reovirus, an oncolytic RNA virus exhibiting antiglioma activity, was shown in a previous single institution phase 1 study found that the inoculation of the virus to be well tolerated in patients with recurrent malignant glioma (MG). The goals of multicenter study reported herein were to determine the dose-limiting toxicity, maximum tolerated dose, and target lesion response rate when reovirus was administered in a novel fashion via intratumoral infusion for 72 hours in patients with recurrent malignant glioma. Fifteen adult patients were treated in a dose escalation study ranging from 1 × 10(8) to 1 × 10(10) tissue culture infectious dose 50, tentimes the dose achieved in the previous trial. Neurological, functional examinations, and imaging studies were completed pre- and postinfusion. There was one grade 3 adverse event (convulsions) felt to be possibly related to treatment, but no grade 4 adverse events considered probably or definitely related to treatment. Dose-limiting toxicity were not identified and a maximum tolerated dose was not reached. Evidence of antiglioma activity was seen in some patients. This first report of intratumoral infusion of reovirus in patients with recurrent malignant glioma demonstrated the approach to be safe and well tolerated, warranting further studies.


Assuntos
Glioma/terapia , Recidiva Local de Neoplasia/terapia , Terapia Viral Oncolítica , Reoviridae/genética , Adulto , Idoso , Feminino , Glioma/genética , Glioma/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/virologia , Vírus Oncolíticos/genética , Vírus Oncolíticos/patogenicidade
10.
Clin Cancer Res ; 17(3): 581-8, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21106728

RESUMO

PURPOSE: This study combined systemic administration of the oncolytic reovirus type 3 Dearing (reovirus) with chemotherapy in human subjects. We aimed to determine the safety and feasibility of combining reovirus administration with gemcitabine and to describe the effects of gemcitabine on the antireoviral immune response. EXPERIMENTAL DESIGN: Patients received reovirus in various doses, initially we dosed for five consecutive days but this was poorly tolerated. We amended the protocol to administer a single dose and administered up to 3 × 10(10) TCID(50). Toxicity was assessed by monitoring of clinical and laboratory measurements. We assessed antibody response by cytotoxicity neutralization assay. RESULTS: Sixteen patients received 47 cycles of reovirus. The two initial patients and one patient in the final cohort experienced dose limiting toxicity (DLT). The DLTs consisted of two asymptomatic grade 3 liver enzyme rises and one asymptomatic grade 3 troponin I rise. Common toxicities consisted of known reovirus and gemcitabine associated side effects. Further analysis showed a potential interaction between reovirus and gemcitabine in causing liver enzyme rises. Grade 3 rises in liver enzymes were associated with concomitant aminocetophen use. Importantly, the duration of the liver enzyme rise was short and reversible. Neutralizing antibody responses to reovirus were attenuated both in time-to-occurrence and peak height of the response. CONCLUSIONS: Reovirus at the dose of 1 × 10(10) TCID(50) can be safely combined with full dose gemcitabine. Combination of reovirus with gemcitabine affects the neutralizing antibody response and this could impact both safety and efficacy of this treatment schedule.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Orthoreovirus Mamífero 3 , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Adulto , Idoso , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Feminino , Humanos , Injeções Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/imunologia , Terapia Viral Oncolítica/efeitos adversos
11.
Invest New Drugs ; 28(5): 641-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19572105

RESUMO

BACKGROUND: Reolysin is reovirus serotype 3-Dearing strain, a double-stranded replication-competent RNA non-enveloped icosahedral virus. It induces cytopathic and anti-cancer effects in cells with an activated ras pathway due to inhibition of the dsRNA-activated protein kinase. METHODS: This was a single center dose escalation trial of Reolysin administered intravenously every 4 weeks in doses ranging from 1 x 10(8) to 3 x 10(10) tissue culture infective dose (TCID)(50). Serum for neutralizing antibody, and serum, stool, saliva, and urine for viral shedding were collected. Tumor samples were analyzed for activating mutations in the ras and braf oncogenes. RESULTS: Eighteen patients received 27 doses of Reolysin in 6 dose cohorts accomplishing a 300 fold dose escalation without a protocol-defined dose limiting toxicity. Drug related grade 2 toxicities included fatigue and fever (1 patient each). All patients developed neutralizing antibody during the course of the study. Viral shedding was observed in 6 patients. One patient with anthracycline and taxane refractory breast cancer experienced a partial response (PR) and her tumor had a ras G12A mutation. Biopsy from her chest wall mass showed evidence of necrosis and viral replication by electron microscopy. Overall clinical benefit (1 PR + 7 stable disease) rate was 45%, and appeared higher in patients with viral shedding (67%) than those without (33%). CONCLUSION: Reolysin administered monthly as a one-hour infusion is safe and well-tolerated even in multiple doses. Reolysin has anti-tumor activity as a single agent warranting further evaluation, including in combination with chemotherapy. Viral shedding may suggest intrapatient replication yielding a benefit and should be studied carefully in future studies.


Assuntos
Antineoplásicos/administração & dosagem , Orthoreovirus Mamífero 3/fisiologia , Neoplasias/terapia , Replicação Viral/fisiologia , Adulto , Idoso , Formação de Anticorpos/imunologia , Antineoplásicos/efeitos adversos , Análise Mutacional de DNA , Feminino , Humanos , Injeções Intravenosas , Masculino , Orthoreovirus Mamífero 3/ultraestrutura , Pessoa de Meia-Idade , Mutação/genética , Neoplasias/imunologia , RNA Viral/sangue , RNA Viral/urina
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