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1.
J Surg Res ; 265: 272-277, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33964637

RESUMO

INTRODUCTION: Iatrogenic ureteral injury (IUI) is an uncommon complication in colorectal surgery. Prophylactic ureteral stenting (PUS) gained acceptance to aid in intraoperative identification of the ureter. Despite its use, the benefit of pus to avoid IUI remains debatable. We sought to analyze the rates of IUI after colorectal surgery in veterans and to compare the outcomes after PUS using a large matched cohort. METHODS: The veterans affairs surgical quality improvement program database was queried for patients who underwent colorectal surgery from 2008-2015. To analyze the outcomes of PUS, we created two matched groups using propensity-score matching accounting for demographical and clinical cofactors to assess variable outcomes. Cross-tabulation was used to calculate rates of IUI and univariate and multivariate analyses were performed to evaluate risk factors associated with IUI. RESULTS: 27,448 patients were identified and 458 underwent PUS placement (1.6%). The majority of procedures were performed electively and with an open approach. Mean age was 65 y, 96.3% were male, and colorectal cancer was the most common indication. 45 patients (0.2%) were diagnosed with IUI. IUI incidence was higher in female patients, after left-sided colorectal resection, and in those undergoing open procedures. After matching, PUS use was associated with longer length of stay and operative time and increased creatinine levels from baseline. CONCLUSION: We demonstrated that the use of PUS is independently associated with increased operative time and change in creatinine levels. Although no IUI occurred in the PUS group, this finding was not statistically significant. The risk and/or benefit ratio of PUS should be considered for each individual case, with its selective use based on the presence of risk factors for IUI, such as female patients and left-sided resections.


Assuntos
Cirurgia Colorretal/efeitos adversos , Complicações Pós-Operatórias/prevenção & controle , Stents/estatística & dados numéricos , Ureter/lesões , Idoso , Feminino , Humanos , Doença Iatrogênica/prevenção & controle , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos
2.
Surg Endosc ; 35(10): 5558-5566, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33025254

RESUMO

INTRODUCTION: We hypothesize that the recent trend in performing cholecystectomy in US Veterans shows wide adoption of the laparoscopic technique and improvement in the outcome following both laparoscopic (LC) and open cholecystectomy (OC). This study utilizes the Veterans Affairs Surgical Quality Improvement Program database to examine the status and outcome of cholecystectomy. METHODS: A retrospective review of veterans who underwent cholecystectomy between 2008 and 2015 was performed. Data analysis included patient demographics, operations, and postoperative outcomes. Cochran-Armitage trend analysis was used to assess significant changes in outcome over the study period. p ≤ 0.05 was considered significant. RESULTS: A total of 40,722 patients (average age of 61 years) were included in the study (males 85.6%). LC was performed in the majority of patients (86.4%). Patients in the OC group (13.6%) were more likely to have advanced age (≥ 65 years) (47.6% vs 32.0%, p < 0.001) and higher ASA class (III-V) (81.9% vs 65.4%, p < 0.001) than those in the LC group. Compared with LC, OC had higher mortality rates at 30 days (1.3% vs 0.3%; OR = 1.6, p = 0.03), 3 months (2.6% vs 0.7%; OR = 1.7, p < 0.001), 6 months (3.9% vs 1.1%; OR = 1.5, p < 0.001) and 1 year (5.7% vs 2.0%; OR = 1.5, p < 0.001); higher rates of morbidity, including pneumonia (OR = 1.9, p < 0.001), deep venous thrombosis (OR = 2.4, p = 0.02), reoperation (OR = 1.8, p < 0.001), and superficial (OR = 4.9, p < 0.001) and deep (OR = 1.5, p = 0.01) surgical site infections; and a longer length of stay (6.5 days vs 2.6 days, p < 0.001). Trend analysis showed a significant decrease in both mortality (p = 0.02) and morbidity (p < 0.001) for LC over the study period, but no improvement in mortality (p = 0.35) and a only a minimal improvement in morbidity (p = 0.04) for OC. CONCLUSION: In the recent era, LC has been widely performed in the VA with significant improvement in outcome. Efforts are needed to adopt alternative approaches to planned OC and to improve postoperative outcomes.


Assuntos
Colecistectomia Laparoscópica , Veteranos , Idoso , Colecistectomia , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos
3.
Adv Exp Med Biol ; 1290: 51-65, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33559854

RESUMO

Unlike other malignancies, ovarian cancer (OC) creates a complex tumor microenvironment with distinctive peritoneal ascites consisting of a mixture of several immunosuppressive cells which impair the ability of the patient's immune system to fight the disease. The poor survival rates observed in advanced stage OC patients and the lack of effective conventional therapeutic options have been attributed in large part to the immature dendritic cells (DCs), IL-10 secreting regulatory T cells, tumor-associated macrophages, myeloid-derived suppressor cells, and cancer stem cells that secrete inhibitory cytokines. This review highlights the critical role played by the intraperitoneal presence of IL-10 in the generation of an immunosuppressive tumor microenvironment. Further, the effect of antibody neutralization of IL-10 on the efficacy of DC and chimeric antigen receptor T-cell vaccines will be discussed. Moreover, we will review the influence of IL-10 in the promotion of cancer stemness in concert with the NF-κB signaling pathway with regard to OC progression. Finally, understanding the role of IL-10 and its crosstalk with various cells in the ascitic fluid may contribute to the development of novel immunotherapeutic approaches with the potential to kill drug-resistant OC cells while minimizing toxic side effects.


Assuntos
Interleucina-10 , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Células Dendríticas , Feminino , Humanos , Neoplasias Ovarianas/terapia , Transdução de Sinais , Microambiente Tumoral
4.
Pharm Res ; 28(12): 3079-90, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21818714

RESUMO

PURPOSE: MicroRNA-101 (miR-101) expression is negatively associated with tumor growth and proliferation in several solid epithelial cancers. Enhancer of zeste homolog 2 (EzH2) appears to be a functional target of miR-101. We explore the role of miR-101 and its interaction with EzH2 in epithelial ovarian carcinoma (EOC). METHODS: In situ hybridization (ISH) for miR-101 was performed on EOC patient tissues and normal controls. EOC cell lines were transfected with miR-101 and subjected to growth analysis and clonogenic assays. Cell motility was assessed by Boyden chamber and wound-healing assays. P21(waf1/cip1) and EzH2 interaction was assessed by Chromatin Immunoprecipitation (ChIP) assay in MDAH-2774 cells. SCID mice were assessed for tumor burden after injection with miR-101 or control vector-treated MDAH-2774 cells. RESULTS: ISH analysis revealed a decrease in miR-101 expression in EOC compared with normal tissue. MiR-101 re-expression in EOC cell lines resulted in increased apoptosis, decreased cellular proliferation, invasiveness, and reduced growth of tumor xenografts. CHIP assays revealed that re-expression of miR-101 inhibited the interaction of EzH2 with p21(waf1/cip1) promoter. CONCLUSIONS: MiR-101 re-expression appears to have antitumor effects, providing a better understanding of the role of miR-101 in EOC.


Assuntos
Cromatina/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Proteínas de Ligação a DNA/genética , MicroRNAs/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fatores de Transcrição/genética , Animais , Apoptose , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Proliferação de Células , Cromatina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos SCID , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Ovário/patologia , Complexo Repressor Polycomb 2 , Fatores de Transcrição/metabolismo
5.
Am J Surg ; 221(3): 538-542, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33358373

RESUMO

BACKGROUND: This study examines the outcomes of open and laparoscopic cholecystectomy (OC/LC) in veterans with cirrhosis and develops a nomogram to predict outcomes. METHODS: We analyzed the Veterans Affairs Surgical Quality Improvement Program to identify all patients with cirrhosis and ascites who underwent cholecystectomy from 2008 to 2015. Univariate and multivariate regression were used to identify predictors of morbidity and mortality. A predictive nomogram was constructed and internally validated. RESULTS: A total of 349 patients were identified. Overall, complications occurred in 18.7% of patients, and mortality was 3.8%. LC was performed in 58.9%, and 19.2% were preformed emergently. Overall, Model for End-Stage Liver Disease score was an independent factor of morbidity and mortality, while laparoscopic approach had a protective effect on morbidity. CONCLUSIONS: Although cholecystectomy is a high-risk operation in cirrhotic veterans, LC may have favorable outcomes than OC in selected patients. An easy-to-use nomogram to predict morbidity and mortality for cirrhotic patients undergoing cholecystectomy is proposed.


Assuntos
Colecistectomia Laparoscópica , Cálculos Biliares/complicações , Cálculos Biliares/cirurgia , Cirrose Hepática/complicações , Complicações Pós-Operatórias/epidemiologia , Veteranos , Idoso , Feminino , Cálculos Biliares/mortalidade , Humanos , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Nomogramas , Valor Preditivo dos Testes , Melhoria de Qualidade , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos
6.
Surgery ; 169(3): 603-609, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33077198

RESUMO

BACKGROUND: Ventral hernia repair is a common procedure with reported 15% to 37% morbidity and 0.3% to 1.4% mortality rates. This study examines the 30-day morbidity and mortality of open and laparoscopic ventral hernia repair in veterans, along with the impact of body mass index on these outcomes. METHODS: The Veterans Affairs Surgical Quality Improvement Program was queried for all ventral hernia repairs during the period 2008 to 2015. In this retrospective analysis, we compared outcomes of open ventral hernia repair versus laparoscopic ventral hernia repair and among different body mass index classes. RESULTS: A total of 19,883 patients were identified (92.6% male, mean age 59.7, 53.1% obese, and 71.6% with American Society of Anesthesiologists class ≥III). There were 95 (0.5%) mortalities, and complications occurred in 1,289 (6.5%) patients. Open ventral hernia repair was performed in 60.2%; 14.5% were recurrent, and 3.3% were performed as an emergency operation. When compared with open ventral hernia repair, the laparoscopic ventral hernia repair group had higher mean body mass index, less patients with American Society of Anesthesiologists class ≥III, fewer emergency operations, longer operative time, less complications, decreased mortality, and shorter duration of stay. Body mass index 35.00 to 49.99 was predictive of overall complications in the open ventral hernia repair group. CONCLUSION: Ventral hernia repair can be performed in the veteran population with outcomes comparable to those in the private sector. Morbid obesity has a negative impact on ventral hernia repair outcomes that is most prominent following open surgery. Laparoscopic ventral hernia repair may offer superior outcomes when compared to open ventral hernia repair and may be considered.


Assuntos
Hérnia Ventral/epidemiologia , Hérnia Ventral/cirurgia , Herniorrafia , Serviços de Saúde para Veteranos Militares , Veteranos , Adulto , Idoso , Índice de Massa Corporal , Comorbidade , Feminino , Hérnia Ventral/etiologia , Herniorrafia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Duração da Cirurgia , Cuidados Pré-Operatórios , Fatores de Risco , Resultado do Tratamento
7.
J Emerg Med ; 39(5): 696-700, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19327938

RESUMO

BACKGROUND: The very unusual association between herpes zoster and Ogilvie syndrome has received scant attention in the published literature. OBJECTIVES: This review discusses the published experience since 1950 and attempts to increase clinical awareness about the co-existence of both conditions. CASE REPORT: An 84-year-old male patient affected by herpes zoster presented with advanced acute colonic pseudo-obstruction and was successfully treated with colonic diversion. DISCUSSION: Twenty published studies (1950-2008) of 28 patients in whom the two conditions co-existed are reviewed. The review included 22 male and 7 female patients (24%) aged 32-87 years (mean, 61 years). Significant co-morbidities were present in 45% of the patients. The majority of patients were observed and treated conservatively (83%). Two patients died (7%), both suffering from respiratory complications and malignancy. CONCLUSION: Recognition of the combined syndrome may help to avoid unnecessary surgery. Laparotomy should be reserved as a last resort for when the obstruction cannot be successfully managed by endoscopy. A diverting colostomy can be used to monitor the blood supply and thus provide early warning for an impending abdominal catastrophe.


Assuntos
Pseudo-Obstrução do Colo/epidemiologia , Herpes Zoster/epidemiologia , Idoso de 80 Anos ou mais , Bloqueio Atrioventricular/epidemiologia , Pseudo-Obstrução do Colo/diagnóstico por imagem , Pseudo-Obstrução do Colo/cirurgia , Colonoscopia , Colostomia , Comorbidade , Descompressão Cirúrgica , Humanos , Masculino , Tomografia Computadorizada por Raios X
8.
J Immunol Methods ; 340(1): 48-54, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18996128

RESUMO

Acute rejection (AR) remains a significant complication in renal transplant patients. Using serum creatinine for AR screening has proven problematic, and thus a noninvasive, highly sensitive and specific test is needed. T cells from human peripheral blood were analyzed using Raman spectroscopy. Fifty-one Mixed Lymphocyte Culture (MLC) activated T cells (ATC), 28 Mitomycin C inactivated T cells (ITC), and 35 resting T cells (RTC), were studied utilizing 785 and 514.5 nm wavelengths. Statistical analysis following subtraction of fluorescence used Student's t test to quantify peak ratio differences and discriminant function analysis (DFA), with three distinct sectors assigned for grouping purposes: Sector I, ITC; Sector II, ATC; Sector III, RTC. Differences between ATC and non-activated T cells (ITC and RTC) were found at 1182 and 1195 cm-1 peak positions for both wavelengths. Significant differences in peak ratios for 785 and 514.5 nm wavelengths existed between ATC and RTC (p=0.001 and p=0.006, respectively) and ATC and ITC (p=0.001 and p=0.001, respectively), with a trend in differences observed between ITC and RTC (p=0.07 and p=0.08, respectively). Analysis of the DFA-derived sector distribution for the 785 and 514.5 nm wavelengths revealed a sensitivity of 95.7% and 89.3%, respectively, and a specificity of 100% and 93.8%, respectively. This data suggests that Raman spectroscopy can detect significant differences between activated and nonactivated T cells based upon cell-surface receptor expression, thereby establishing unique signatures that can aid in the development of a noninvasive AR screening tool with high sensitivity and specificity.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Rim/imunologia , Análise Espectral Raman/métodos , Linfócitos T/imunologia , Análise Discriminante , Rejeição de Enxerto/diagnóstico , Humanos , Ativação Linfocitária , Análise Espectral Raman/instrumentação
9.
Cytometry A ; 75(11): 917-23, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19753631

RESUMO

Acute rejection (AR) remains problematic in renal transplantation. As a marker, serum creatinine is limited, warranting a more effective screening tool. Raman spectroscopy (RS) can detect T-cell activation with high sensitivity. In this study we explore its specificity. Seventy-five inactivated, 40 alloantigen-activated, and 75 CD3/CD28-activated T cells were analyzed using RS. CD3/CD28-activated peak magnitudes (PM) were 4.3% to 23.9% lower than inactivated PM at positions: 903, 1031, 1069, 1093, 1155, 1326, and 1449 cm(-1), with a difference in peak ratio (PR) observed at the 1182:1195 cm(-1) position (0.91 +/- 0.06 vs. 1.2 +/- 0.01, respectively: P = 0.006). Differences in CD3/CD28- and alloantigen-activated PM were observed at: 903, 1031, 1093, 1155, 1326, and 1449 cm(-1), with no PR differences at the 1182:1195 cm(-1) position (0.91 +/- 0.06 vs. 0.86 +/- 0.09: P = 0.8). Spectral signature separation of CD3/CD28-and alloantigen-activated groups was 100% specific and sensitive. We conclude that RS can differentiate T cells activated by different stimuli with high sensitivity and specificity.


Assuntos
Antígenos CD28/biossíntese , Complexo CD3/biossíntese , Rejeição de Enxerto/diagnóstico , Transplante de Rim/métodos , Análise Espectral Raman/métodos , Linfócitos T/imunologia , Diferenciação Celular , Membrana Celular/metabolismo , Separação Celular , Rejeição de Enxerto/patologia , Humanos , Leucócitos Mononucleares/citologia , Ativação Linfocitária/imunologia , Linfócitos T/metabolismo
10.
Clin Transplant ; 23(2): 150-6, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-18713260

RESUMO

Subclinical rejection (SCR) is quite common early following renal transplantation and decreases progressively with time. The immunological profile of the recipient, the immunosuppressive regimen used, and the occurrence of prior episodes of clinical acute rejection (AR) are all risk factors for SCR. SCR, in turn, is a risk factor for chronic interstitial and tubular fibrosis and has been associated with worse glomerular filtration rate (GFR) and graft survival. Early SCR should be initially treated with pulse steroids. SCR is a form of biopsy-proven AR and, particularly if treated, must be fairly reported and displayed as a solid endpoint in clinical studies.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Rim/imunologia , Doença Aguda , Taxa de Filtração Glomerular , Glucocorticoides/administração & dosagem , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/tratamento farmacológico , Humanos , Pulsoterapia , Fatores de Risco
11.
Clin Transplant ; 23(4): 454-61, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19191806

RESUMO

The relative importance of donor and recipient risk factors in predicting outcomes in African-American (AA) renal allograft recipients receiving contemporary immunosuppression, including early steroid withdrawal, has not been previously examined. We assessed the impact of 21 risk factors on five primary outcomes in 132 deceased-donor AA renal allograft recipients transplanted from July 2001 to August 2006 with follow-up 6-67 (mean 35 +/- 17) months by univariate and multivariate analysis. Thymoglobulin or basiliximab was given for induction, and mycophenolate mofetil with either tacrolimus or sirolimus (SRL) +/- prednisone for maintenance. Non-compliance accounted for 26% of graft loss (GL) and 19% of acute rejection (AR) episodes, and was more prevalent in patients who were HCV+ and those on prednisone. Delayed graft function remained a significant predictor of GL, but not via increased AR, and donor ethnicity emerged as an important predictor of patient death. De novo use of SRL resulted in increased AR, and only increased recipient age significantly predicted new-onset diabetes mellitus. Our preliminary results suggest the need for improvements in patient education, pre-transplant psychosocial assessment, and late post-transplant psychosocial support and can be utilized to help guide donor/recipient selection and tailor immunosuppressive management to optimize outcomes in this challenging group of patients.


Assuntos
Negro ou Afro-Americano , Glucocorticoides/administração & dosagem , Rejeição de Enxerto , Imunossupressores/administração & dosagem , Transplante de Rim/etnologia , Prednisona/administração & dosagem , Adulto , Cadáver , Esquema de Medicação , Feminino , Sobrevivência de Enxerto , Humanos , Transplante de Rim/efeitos adversos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo
12.
Pediatr Transplant ; 13(4): 490-4, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18992052

RESUMO

DCZ, an IL-2 receptor antagonist, has been widely used for induction therapy in pediatric and adult solid organ transplantation. Originally, it was recommended as a five-dose regimen; however, fewer doses may be efficacious and less costly for prevention of rejection. There is limited experience with the use of fewer doses in pediatric renal transplantation. We retrospectively reviewed the outcomes of 26 primary pediatric renal transplants performed at a single center between June 2004 and May 2007 receiving induction therapy with two-dose DCZ (1.5 mg/kg preoperatively and day seven post-transplant). Maintenance immunosuppression included tacrolimus, MMF, and prednisone in all patients. Forty-six percent were African American and 92% were deceased-donor transplants. After a mean follow-up of 17.8 +/- 7.5 months, acute rejection was noted in 11.5% and graft survival was 92.3%. CMV infection occurred in 11.5%, but no case of BK nephropathy or post-transplant lymphoproliferative disorder was observed. Our preliminary results suggest that induction therapy with two-dose DCZ was convenient, economical, and effective in preventing rejection episodes without an increase in adverse events or hospital stay. Larger randomized clinical trials with longer duration of follow-up are needed to more fully validate the use of this regimen in pediatric renal transplantation.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Imunoglobulina G/administração & dosagem , Imunossupressores/administração & dosagem , Falência Renal Crônica/cirurgia , Transplante de Rim , Adolescente , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Daclizumabe , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Estudos Retrospectivos
13.
Surgery ; 166(4): 503-508, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31416604

RESUMO

BACKGROUND: We have previously demonstrated in vitro cytotoxicity of mesothelin-chimeric antigen receptor autologous T cells against pancreatic cancer cells using lentiviral vectors, but these vectors pose safety concerns. Here, we incorporated Sleeping Beauty and minicircle design enhancements into interleukin-2-secreting natural NK-92MI cells to eliminate both bacterial and viral components and address inhibition by the tumor microenvironment. METHODS: Parental (conventional deoxyribonucleic acid)-mesothelin-chimeric antigen receptor and minicircle-mesothelin-chimeric antigen receptor vectors were electroporated into NK-92MI cells and engraftment was visualized by immunofluorescence analysis with protein-L staining. Interferon-γ and granzyme B secretion were measured by enzyme-linked immunosorbent assay from cocultures of parental-mesothelin-chimeric antigen receptors and minicircle-mesothelin-chimeric antigen receptors with human pancreatic cancer cells, and cytotoxicity of chimeric antigen receptor NK-92MI cells was tested against three pancreatic cancer cell lines. RESULTS: Cloning of mesothelin-chimeric antigen receptor Sleeping Beauty into a minicircle vector removed its bacterial backbone and reduced its size with improved electroporation efficiency. Chimeric antigen receptor engraftment, Interferon-γ and granzyme B secretion, and specific lysis against all three pancreatic cancer lines were significantly increased with minicircle-mesothelin-chimeric antigen receptor versus parental-mesothelin-chimeric antigen receptor NK-92MI cells. CONCLUSION: We provide proof of concept that allogeneic mesothelin-chimeric antigen receptor NK-92MI cells with hybrid Sleeping Beauty and minicircle technologies provide increased engraftment and cytotoxicity in vitro with potential safety benefits when translated to the clinical arena.


Assuntos
Morte Celular/imunologia , Proteínas Ligadas por GPI/farmacologia , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Neoplasias Pancreáticas/patologia , Receptores de Antígenos Quiméricos/imunologia , Linhagem Celular Tumoral , Eletroporação/métodos , Ensaio de Imunoadsorção Enzimática , Humanos , Técnicas In Vitro , Células Matadoras Naturais/efeitos dos fármacos , Mesotelina , Neoplasias Pancreáticas/terapia , Sensibilidade e Especificidade , Microambiente Tumoral
14.
Transplantation ; 86(2): 269-74, 2008 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-18645490

RESUMO

BACKGROUND: Only four centers have reported their results with renal transplantation in human immunodeficiency virus (HIV)+ recipients on highly active antiretroviral therapy, and acute rejection (AR) rates have consistently ranged from 43% to 67%. METHODS: We examined the outcomes of eight adult HIV+ primary renal allograft recipients with median 15 (range 8-47) months follow-up with multiple other high-risk factors, including African American ethnicity, hepatitis C virus (HCV) positivity, long waiting times, prior sensitization, paucity of live donors, and delayed graft function. Our immunosuppressive protocol consisted of an anti-interleukin-2 receptor antibody for induction, and mycophenolate mofetil, cyclosporin A, and prednisone for maintenance. Initial and 3- to 6-month cyclosporin A trough level targets were 250 to 300 and 225 to 275 ng/mL, respectively, and mycophenolate mofetil dose was adjusted according to 2 to 4 week surveillance and subsequent as needed mycophenolic acid predose concentrations during the first 6 months. RESULTS: Patient and graft survival were 100% and 88%, respectively, with an AR rate of 13% and excellent renal function. No patients developed new-onset diabetes, opportunistic or other serious infections, malignancy, or progression of hepatitis C virus-related liver disease. Excellent suppression of HIV replication with maintenance of CD4 counts was noted in all cases. CONCLUSIONS: Our findings suggest that HIV+ patients on highly active antiretroviral therapy can undergo successful renal transplantation with a low incidence of both AR and AIDS-associated and non-AIDS associated infections, despite associated risk factors for poorer outcome. Our encouraging but preliminary results with this protocol will need to be verified in larger numbers of HIV+ renal allograft recipients with longer follow-up.


Assuntos
Infecções por HIV/complicações , Transplante de Rim/métodos , Insuficiência Renal/complicações , Insuficiência Renal/terapia , Adulto , Terapia Antirretroviral de Alta Atividade , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Hepatite C/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-2/química , Fatores de Risco , Resultado do Tratamento
15.
Surgery ; 163(3): 627-632, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29336814

RESUMO

BACKGROUND: Pancreatic cancer cells are known to shield themselves from immunosurveillance by secreting immune inhibitory cytokines such as Interleukin-10. Using mesothelin, a differentiating antigen that is overexpressed in pancreatic cancer, we assessed the negative effect of the tumor microenvironment on chimeric antigen receptor T cell-based immunotherapy and its reversal via depletion of Interleukin-10. METHODS: T cells cultured in pancreatic cancer-cell-conditioned medium were transduced with lentiviruses encoding mesothelin-chimeric antigen receptor in the presence or absence of anti-Interleukin-10-blocking antibody. RESULTS: Coculture supernatants of conditioned medium displayed significant inhibition of interferon γ and granzyme B secretion, both of which are crucial for induction of target cell cytotoxicity. In contrast, this inhibition was restored toward baseline when conditioned medium was Interleukin-10- depleted (p < .05 for both interferon γ and granzyme B). In addition, we observed a significant decrease in mesothelin-chimeric antigen receptor T cell-induced cytotoxicity of BxPC-3 target cells in the presence of conditioned medium. Furthermore, we observed a partial blunting of this inhibition when Interleukin-10 was depleted from the conditioned medium. CONCLUSION: Substantial reversal of tumor-derived immunosuppression may be achieved by blocking Interleukin-10 in the local microenvironment, allowing for more effective cytotoxicity of mesothelin-engrafted chimeric antigen receptor T cells and enhancing the potential for clinical application.


Assuntos
Proteínas Ligadas por GPI/farmacologia , Interleucina-10/fisiologia , Neoplasias Pancreáticas/patologia , Linfócitos T/fisiologia , Microambiente Tumoral/fisiologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Humanos , Imunoterapia , Mesotelina , Receptores de Antígenos de Linfócitos T
16.
Transplantation ; 83(5): 546-9, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17353771

RESUMO

BACKGROUND: There is limited experience with the use of cinacalcet in the treatment of persistent secondary hyperparathyroidism after kidney transplantation. METHODS: We retrospectively analyzed our experience in 18 renal allograft recipients who initiated cinacalcet therapy from 1 month to 23 years (median 3 years) posttransplantation and were maintained on the drug for 6 months. The daily dose was titrated from 30 mg up to a maximum of 180 mg to achieve a reduction in serum intact parathyroid hormone (PTH) levels. RESULTS: Sustainable, significant decreases in mean calcium and alkaline phosphatase were noted at 1 month and intact PTH by 3 months, with 50% of patients achieving at least a 30% drop in PTH levels at 6 months. Serum phosphorous increased at 6 months, whereas urine N-telopeptides decreased. There were no significant changes in serum osteocalcin, albumin, and hemoglobin levels. We did not observe a tachyphylaxis phenomenon. Two patients reported occasional nausea, but did not require medication discontinuation. Estimated glomerular filtration rate did decrease progressively over the 6-month period. CONCLUSION: Cinacalcet appears to be an effective drug for the treatment of posttransplant hypercalcemia due to persistent secondary hyperparathyroidism. Further studies with more patients and longer follow-up will be needed to better elucidate the efficacy/safety profile for this agent, particularly with regard to long-term bone histology and renal outcomes.


Assuntos
Hiperparatireoidismo Secundário/tratamento farmacológico , Transplante de Rim/fisiologia , Naftalenos/uso terapêutico , Adulto , Idoso , Cálcio/sangue , Cinacalcete , Feminino , Seguimentos , Humanos , Hiperparatireoidismo Secundário/etiologia , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fósforo/sangue , Estudos Retrospectivos
17.
Surgery ; 142(4): 538-44; discussion 544-5, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17950346

RESUMO

BACKGROUND: There is a paucity of data regarding the use of early corticosteroid withdrawal (ESW) in African-American renal allograft recipients, and very few reports with >or=1 year follow-up in all patients. METHODS: We examined the outcomes of 57 African-American renal allograft recipients with minimum follow-up 12 months who did not receive maintenance steroids after day 4 posttransplant. All patients received thymoglobulin induction, mycophenolate mofetil, and initial tacrolimus (n = 48) or sirolimus (n = 9). RESULTS: Patient and graft survival were 98% and 96% at 1 year, and 95% and 89% over the entire follow-up period (mean, 23 +/- 8 months). Incidence of acute rejection and cytomegalovirus infection were 18% and 7%, respectively, with mean serum creatinine 1.6 +/- 0.5 and 1.7 +/- 0.9 mg/dL at 6 and 12 months. Of patients with functioning grafts, 84% remained steroid free at 1 year, of which 11 (24%) were also calcineurin inhibitor free. Twenty-seven patients underwent surveillance biopsy at 1 month and 28 at 12 months, with 15 surveyed at both time points. There were significant increases in only 2 of the 6 1997 Banff chronic allograft nephropathy (CAN) category scores in this subgroup, with all mean values remaining <1 (mild in severity) at 1 year. Overall, from 82% to 96% of the 12-month scores were

Assuntos
Corticosteroides/administração & dosagem , Negro ou Afro-Americano/estatística & dados numéricos , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etnologia , Transplante de Rim/etnologia , Transplante de Rim/estatística & dados numéricos , Doença Aguda , Adulto , Biópsia/estatística & dados numéricos , Seguimentos , Sobrevivência de Enxerto , Humanos , Terapia de Imunossupressão , Incidência , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Transplante Homólogo , Resultado do Tratamento
18.
Transplantation ; 82(1): 136-9, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16861954

RESUMO

Little is known about the use of histidine-tryptophan-ketoglutarate (HTK) preservation solution for pancreas preservation. We compared early pancreas graft outcomes at four pancreas transplant programs within the state of Michigan in 2002 and 2003 (University of Wisconsin [UW] era) with those in 2004 (HTK era). The primary endpoint was early graft loss. The UW group (n=41) and the HTK group (n=36) had similar outcomes with respect to: technical graft loss (9.8% vs. 8.3%, P=NS), 90-day graft function (90.2% vs. 86.1%, P=NS), and rate of pancreatic leak/abscess (12.2% vs. 11.1%, P=NS). There were also no significant differences in postoperative amylase and lipase levels between the two groups. The HTK group did have significantly more acute rejection within the first 180 days (25.0% vs. 9.8%, P<0.05). HTK is a suitable substitute for UW in the preservation of pancreas allografts.


Assuntos
Soluções para Preservação de Órgãos/farmacologia , Transplante de Pâncreas , Pâncreas/efeitos dos fármacos , Adulto , Feminino , Glucose/farmacologia , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Masculino , Manitol/farmacologia , Cloreto de Potássio/farmacologia , Procaína/farmacologia
20.
Transplantation ; 79(6): 716-21, 2005 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-15785379

RESUMO

BACKGROUND: It has been suggested that the use of antilymphocyte induction therapy in African-American (AA) renal transplant recipients reduces the risk of acute rejection (AR) and improves graft survival. It is not clear whether the efficacy of basiliximab (BSX) is different from that of Thymoglobulin (ATG) in this regard. METHODS: We retrospectively assessed the effect of induction therapy with BSX versus ATG in 88 AA renal allograft recipients receiving transplants at our center between July 2001 and June 2003 and followed for 19+/-7 months. All patients were maintained on mycophenolate mofetil, prednisone, and either tacrolimus or sirolimus. Study endpoints included patient and graft survival, graft function, and incidence of AR and cytomegalovirus infection. Regression models were used to evaluate the independent effect of each induction agent on these endpoints. RESULTS: Thirty-six patients received ATG, and 52 received BSX. The groups were comparable with regard to donor race and age, and recipient sex, body mass index, human leukocyte antigen (HLA) matching, and hepatitis C virus serostatus. The ATG group was younger, more likely to receive retransplant, had longer duration of end-stage renal disease and higher panel reactive antibody, and was less likely to receive live-donor organs. However, after adjusting for all these variables, graft outcomes, as well as renal function, were comparable between the two induction groups. We found that the degree of HLA mismatch, delayed graft function, and AR were the only significant predictors of graft loss. CONCLUSION: The results of our study suggest that the choice of induction agent may not have a major impact on graft outcomes in AA renal-allograft recipients.


Assuntos
Anticorpos Monoclonais/imunologia , Soro Antilinfocitário/imunologia , Negro ou Afro-Americano , Sobrevivência de Enxerto/imunologia , Imunoterapia , Transplante de Rim/imunologia , Proteínas Recombinantes de Fusão/imunologia , Adulto , Anticorpos Monoclonais/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Basiliximab , Creatina/sangue , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Modelos de Riscos Proporcionais , Proteínas Recombinantes de Fusão/uso terapêutico , Estudos Retrospectivos , Transplante , Transplante Homólogo/imunologia
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