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1.
Reg Anesth Pain Med ; 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38925711

RESUMO

BACKGROUND: Nerve block utility has been extensively described in the operating room, however, there is a paucity of evidence regarding blocks in the interventional radiology (IR) suite, with no studies examining its safety and efficacy in children. METHODS: A retrospective study was conducted at a single tertiary-care children's hospital to evaluate the analgesic utility of nerve blocks during IR-performed sclerotherapy for bone cysts, venous malformations, and lymphatic malformations. Lymphatic and venous malformations were combined for final analysis. Patients between January 2016 and September 2022 had their medical records reviewed for procedural data, postprocedural pain scores, and analgesic administration data. RESULTS: 309 patients were included in the final analysis. Opioids were required significantly less frequently intraprocedurally and postprocedurally across subgroups. The proportion of patients who received opioids during their hospital course was significant between block and non-block patients, respectively: bone cyst: 62.7% vs 100% (p<0.001); venous and lymphatic malformation: 65.7% vs 97.4% (p<0.001). Average maximum postanesthesia care unit (PACU) pain scores were significantly lower in bone cyst patients with no significant difference seen in pain scores among venous and lymphatic malformation patients. There were no reported nerve block-related complications. DISCUSSION: Nerve blocks demonstrated an opioid-sparing effect intraprocedurally and postprocedurally for all subgroups. Their use among bone cyst patients was associated with significant reductions in average maximum PACU pain scores. Nerve blocks may constitute an effective opioid-sparing component of multimodal analgesia in pediatric patients undergoing IR sclerosis procedures. Prospective data are needed to establish the optimal utility of nerve blocks in the IR setting.

3.
Paediatr Anaesth ; 33(9): 746-753, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37334550

RESUMO

BACKGROUND: Unplanned intraoperative extubation is a rare but potentially catastrophic safety event. Inadvertent extubation in the neonatal and pediatric critical care setting is a recognized quality improvement metric whereas literature for intraoperative extubation is scarce. The aim of this study was to identify risk factors and outcomes associated with unplanned intraoperative extubation. METHODS: We queried the National Surgical Quality Improvement Program-Pediatric database from 2019 to 2020 for patients <18 years of age. A total of 253 673 patients were included in the analysis. Associations between demographics, clinical variables, and unplanned intraoperative extubation were evaluated with univariable and multivariable logistic regression models. The primary outcome was unplanned intraoperative extubation. Secondary outcomes were postoperative pulmonary complication, unplanned reintubation within 24 h, cardiac arrest on day of surgery, and surgical site infection. RESULTS: Unplanned intraoperative extubation occurred in 163 (0.06%) patients. Specific procedures experienced unplanned intraoperative extubation at a higher rate such as bilateral cleft lip repair (1.31% of procedure type) and thoracic repair of tracheoesophageal fistula (1.11% of procedure type). Age, operative time (z-score), American Society of Anesthesiologists Classification 3 and 4, neurosurgery, plastic surgery, thoracic surgery, otolaryngology, and structural pulmonary/airway abnormalities were independent risk factors. Unplanned intraoperative extubation was associated with an increased unadjusted risk for postoperative pulmonary complication (p < .005; OR, 6.05; 95% confidence interval [CI]: 1.93-14.44), unplanned reintubation within 24 h (p < .005; OR, 8.41; 95% CI: 2.08-34.03), cardiac arrest on day of surgery (p < .05; OR, 22.67; 95% CI: 0.56-132.35), and surgical site infection (p < .0005; OR, 3.27; 95% CI 1.74-5.67). CONCLUSIONS: Unplanned intraoperative extubation occurs at a higher frequency in a subset of procedures and patient types. Identifying and targeting at-risk patients with preventative measures may decrease the incidence of unplanned intraoperative extubation and its associated outcomes.


Assuntos
Extubação , Infecção da Ferida Cirúrgica , Recém-Nascido , Criança , Humanos , Extubação/efeitos adversos , Procedimentos Neurocirúrgicos/métodos , Intubação Intratraqueal/efeitos adversos , Fatores de Risco , Estudos Retrospectivos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia
5.
Anesth Analg ; 137(2): 383-391, 2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-36269171

RESUMO

BACKGROUND: The Pediatric Anesthesia COVID-19 Collaborative (PEACOC) is a research network to advance the care of children during the pandemic. Here we calculate the prevalence of coronavirus disease 2019 (COVID-19) among children undergoing anesthesia, look at prevalence in the population data from the Centers for Disease Control and Prevention (CDC), and assess independent risk factors for infection. METHODS: This was a multicenter, retrospective, observational study. Children aged 28 days to 18 years scheduled for anesthesia services at 12 centers requiring universal COVID-19 testing from March 29, 2020 to June 30, 2020 were included. COVID-19 positivity rates among those tested were plotted and trends were assessed using the Cochran Armitage test of trend. Independent risk factors were explored using multivariable logistic regression. RESULTS: Data were collected and analyzed on 33,320 anesthesia encounters including 265 children with COVID-19. Over the study period, the rates of infections in the pediatric anesthesia population did not demonstrate a significant trend. In the general population, there was a significant downward trend in infection rates ( P < .001). In exploratory analysis, multivariable risk factors for a COVID-19 positive test were Black/African American race, Hispanic ethnicity, American Society of Anesthesiologists (ASA) physical status III or above, overweight and obese body mass index (BMI), orthopedic cases, abdominal cases, emergency cases, absence of injury and trauma, and West region (all P < .05). CONCLUSIONS: Rates of COVID-19 in pediatric anesthesia patients were consistently lower than in the general population. Independent risk factors of a positive test for children were identified. This is the first time universal testing for a single infectious disease was undertaken on a wide scale. As such, the association of infection with surgical case type or emergency case status is unprecedented.


Assuntos
Anestesia , COVID-19 , Criança , Humanos , COVID-19/diagnóstico , COVID-19/epidemiologia , Teste para COVID-19 , Estudos Retrospectivos , Prevalência , SARS-CoV-2 , Anestesia/efeitos adversos , Fatores de Risco
6.
Children (Basel) ; 11(1)2023 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-38255335

RESUMO

Arterial catheterization enables continuous hemodynamic monitoring but has been shown to cause severe complications, especially when multiple attempts are required. The aim of this study was to explore what factors were associated with multiple attempts and ultrasound use in the operating room. We performed a retrospective analysis of patients who had arterial catheters inserted at a tertiary care children's hospital from January 2018 to March 2022, identifying clinical factors that were associated with both outcomes. A total of 3946 successful arterial catheter insertions were included. Multivariable analysis showed multiple attempts were associated with noncardiac surgery: pediatric (OR: 1.79, 95% CI: 1.30-2.51), neurologic (OR: 2.63, 95% CI: 1.89-3.57), orthopedic (OR: 3.23, 95% CI: 2.27-4.55), and non-radial artery placement (OR: 5.00, 95% CI: 3.33-7.14) (all p < 0.001). Multivariable analysis showed ultrasound use was associated with neonates (OR: 9.6, 95% CI: 4.1-22.5), infants (OR: 6.98, 95% CI: 4.67-10.42), toddlers (OR: 6.10, 95% CI: 3.8-9.8), and children (OR: 2.0, 95% CI: 1.7-2.5) compared to teenagers, with cardiac surgery being relative to other specialties-pediatric (OR: 0.48, 95% CI: 0.3-0.7), neurologic (OR: 0.27, 95% CI: 0.18-0.40), and orthopedic (OR: 0.38, 95% CI: 0.25-0.58) (all p < 0.001). In our exploratory analysis, increased odds of first-attempt arterial catheter insertion success were associated with cardiac surgery, palpation technique, and radial artery placement. Younger patient age category, ASA III and IV status, cardiac surgery, and anesthesiologist placement were associated with increased odds of ultrasound use.

8.
Paediatr Anaesth ; 32(10): 1121-1128, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35848054

RESUMO

BACKGROUND: Point-of-care hemoglobin testing devices play an important role in intraoperative anesthetic management where significant hemorrhage is anticipated; however, the reliability of these devices has not been examined in the context of pediatric liver transplantation. In this retrospective observational study, we aimed to determine whether 95% of results from two point-of-care hemoglobinometers, the HemoCue and iSTAT, would fall within a difference of ±1 g/dl, our a priori-defined clinically acceptable level of agreement, of the hemoglobin measures on a core laboratory complete blood count. METHODS: We retrospectively collected data from 70 patients presenting for a liver transplant at a single center, tertiary care pediatric hospital over a 3.5-year period. We analyzed 92 contemporaneous pairs of hemoglobin values from the HemoCue and complete blood count, and 252 pairs of hemoglobin values from the iSTAT and complete blood count. Agreement between the point-of-care devices and complete blood count was assessed using Bland-Altman analysis, which was the primary outcome. Secondary analyses included an error grid analysis and Cohen's kappa statistic. RESULTS: Both point-of-care devices underestimated complete blood count hemoglobin values and neither device satisfied our a priori-defined clinically acceptable level of agreement that 95% of values would fall within ±1 g/dl of the complete blood count measurement. The mean difference [limits of agreement] of the HemoCue was 0.4 g/dl (p < .001) [-0.9 to 1.6 g/dl] and of the iSTAT was 0.6 g/dl (p < .001) [-1.4 to 2.6 g/dl]. Secondary error grid analysis revealed that neither device performed well enough to replace a complete blood count at critical thresholds of hemoglobin values. CONCLUSIONS: While the HemoCue and iSTAT contribute information in a timely manner during dynamic intraoperative situations, there is significant imprecision compared to the gold standard complete blood count. If clinical stability allows, the results of these point-of-care hemoglobinometers should be confirmed with a complete blood count, rather than being used as the sole factor in determining transfusion needs during pediatric liver transplantation.


Assuntos
Transplante de Fígado , Sistemas Automatizados de Assistência Junto ao Leito , Perda Sanguínea Cirúrgica , Criança , Hemoglobinas/análise , Humanos , Reprodutibilidade dos Testes , Estudos Retrospectivos
10.
Paediatr Anaesth ; 32(7): 792-800, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35293066

RESUMO

BACKGROUND: Pediatric intravenous catheter insertion can be difficult in the operating room due to the technical challenges of small diameter vessels and the need to rapidly gain intravenous access in anesthetized children. Few studies have examined factors associated with difficult vascular access in the operating room, especially accounting for the increased possibility to use ultrasound guidance. AIMS: The primary aim of the study was to identify factors associated with pediatric difficult vascular access in the operating room. Our primary hypothesis was that Black race, Hispanic ethnicity, and ultrasound use would be associated with pediatric difficult vascular access. METHODS: We performed a retrospective analysis of prospectively collected data from a cohort of pediatric patients who had intravenous catheters inserted in the operating room at an academic tertiary care children's hospital from March 2020 to February 2021. We measured associations among patients who were labeled as having difficult vascular access (>2 attempts at access) with demographic, clinical, and hospital factors. RESULTS: 12 728 intravenous catheter insertions were analyzed. Multivariable analysis showed significantly higher odds of difficult vascular access with Black non-Hispanic race (1.43, 95% CI: 1.06-1.93, p = .018), younger age (0.93, 95% CI: 0.89-0.98, p = .005), overweight (1.41, 95% CI: 1.04-1.90, p = .025) and obese body mass index (1.56, 95% 95% CI: 1.12-2.17, p = .008), and American Society of Anesthesiologists physical status III (1.54, 95% CI:1.11-2.13, p = .01). The attending anesthesiologist compared to all other practitioners (certified registered nurse anesthetist: (0.41, 95% CI: 0.31-0.56, p < .001, registered nurse: 0.25, 95% CI: 0.13-0.48, p < .001, trainee: 0.21, 95% CI: 0.17-0.28, p-value <.001 with attending as reference variable) and ultrasound use (2.61, 95% CI: 1.85-3.69, p < .001) were associated with successful intravenous catheter placement. CONCLUSIONS: Black non-Hispanic race/ethnicity, younger age, obese/overweight body mass index, American Society of Anesthesiologists physical status III, and ultrasound were all associated with pediatric difficult vascular access in the operating room.


Assuntos
Cateterismo Periférico , Salas Cirúrgicas , Criança , Demografia , Humanos , Obesidade , Sobrepeso , Estudos Retrospectivos
11.
BMJ Paediatr Open ; 6(1)2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36645763

RESUMO

Though there is a well-established gender pay gap in medicine, studies on compensation disparities between women and men chief executive officers (CEO) showed mixed results. We conducted a cross-sectional study of children's hospitals in the USA to evaluate whether CEO gender was associated with compensation differences. Nine out of 31 children's hospitals employed a female CEO. There was no significant difference between men and women CEOs in terms of hospital characteristics (location, size or ranking in US News and World report) or CEO characteristics (advanced degrees, tenure or compensation). Gender was not associated with significant differences in CEO compensation.


Assuntos
Diretores de Hospitais , Hospitais Filantrópicos , Masculino , Humanos , Feminino , Criança , Fatores Sexuais , Estudos Transversais , Salários e Benefícios
14.
J Pediatr Surg ; 55(6): 1134-1138, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32199703

RESUMO

BACKGROUND: In 2012, the American Academy of Pediatrics (AAP) concluded the health benefits of circumcision during the neonatal period outweigh the risks. This study describes recent trends in male circumcision in freestanding children's hospitals in the United States. METHODS: Using the Pediatric Health Information System (PHIS), male patients <18 years of age who were circumcised without any additional procedures between the years 2010 and 2017 were identified. Data included age at procedure (neonate: 0-30 days, infant: 31-365 days, early childhood: ≥1 to <5 years, and older child: ≥5 to<18 years), cost, and specialty performing the circumcision. RESULTS: Of the 171,680 circumcisions performed, 85,270 (50%) were during neonatal period, 29,060 (17%) during infancy, 30,276 (18%) early childhood, and 26,355 (16%) thereafter. Circumcision in neonates increased from 39% to 58% (p < 0.001), and the proportion performed during infancy decreased over time. System level cost for ambulatory circumcision averaged $32 million USD annually, and median cost per ambulatory circumcision was $2892 USD. Obstetricians and Pediatricians are performing proportionally more circumcisions. CONCLUSION: Since 2012, proportionally more neonates are undergoing circumcision in US children's hospitals. Perinatal specialties are performing an increasing proportion of circumcisions. Circumcision during the birth hospitalization in the neonatal period is more resource-effective than postponing until later in infancy. TYPE OF STUDY: Retrospective, cross-sectional analysis. LEVEL OF EVIDENCE: Level IV.


Assuntos
Circuncisão Masculina/tendências , Hospitais Pediátricos/tendências , Padrões de Prática Médica/tendências , Adolescente , Distribuição por Idade , Criança , Pré-Escolar , Circuncisão Masculina/economia , Estudos Transversais , Custos Hospitalares/estatística & dados numéricos , Hospitais Pediátricos/economia , Humanos , Lactente , Recém-Nascido , Masculino , Padrões de Prática Médica/economia , Estudos Retrospectivos , Estados Unidos
15.
Br J Anaesth ; 123(5): 618-626, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31540668

RESUMO

BACKGROUND: Preoperative hyponatraemia is an independent risk factor for postoperative mortality in adults. To our knowledge, this has not been investigated in children. METHODS: Using data from the 2014 and 2015 data sets of the American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-P), we conducted a retrospective study of children undergoing surgery. The primary outcome was 30-day all-cause mortality. The secondary outcomes of interest were postoperative seizure within 30 days and prolonged length of stay. To identify any independent association between preoperative hyponatraemia, defined as mild (serum sodium of 131-135 mEq L-1) or severe (≤130 mEq L-1), and death, postoperative seizures, or prolonged length of stay, multivariable logistic regression models were generated. RESULTS: A total of 152 894 patients were identified, and of these 35 291 were included in the final analysis. Preoperative hyponatraemia was present in 5422 patients or 15.4% of the final cohort. There were 432 (0.80%) deaths at 30 days. Compared with patients with a normal preoperative sodium concentration, those with mild (P=0.003; odds ratio [OR]: 1.59; 95% confidence interval [CI]: 1.17-2.18) and severe (P=0.002; OR: 2.16; 95% CI: 1.32-3.54) hyponatraemia had increased rates of death, after adjusting for co-morbidity and procedural complexity. Both mild (P<0.001; OR: 1.53; 95% CI: 1.42-1.65) and severe (P<0.001; OR: 1.51; 95% CI: 1.19-1.93) hyponatraemia were independently associated with prolonged length of stay, after adjusting for relevant co-variates. CONCLUSIONS: This retrospective analysis identified an association between preoperative hyponatraemia and perioperative mortality and length of stay in paediatric patients.


Assuntos
Hiponatremia/mortalidade , Complicações Intraoperatórias/mortalidade , Complicações Pós-Operatórias/mortalidade , Período Pré-Operatório , Chicago/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Estudos Retrospectivos , Fatores de Risco
16.
Paediatr Anaesth ; 29(1): 44-50, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30447169

RESUMO

BACKGROUND: There is a paucity of data regarding risk stratification of pediatric patients presenting for low-risk skin and soft tissue surgery. AIMS: We sought to determine the incidence and independent predictors of postoperative complications and unplanned 30-day readmission in a cohort of children undergoing low-risk skin and soft tissue surgery. METHODS: The study included pediatric patients who underwent minor procedures of the skin and soft tissue at continuously enrolled American College of Surgeons National Surgical Quality Improvement Program Pediatric hospitals over a two-year period. The primary outcome was a 30-day postoperative complication composite. The secondary outcome was unplanned 30-day readmission. RESULTS: The final analysis included 6,730 patients. There were a total of 170 postoperative complications among 152 patients (2.23%) with the majority of complications being either wound-related or postoperative mechanical ventilation. The independent predictors for an increased risk of postoperative complication were American Society of Anesthesiologists classification ≥3 and nutritional deficiency. There were 41 unplanned readmissions (0.61%). The presence of a postoperative wound complication or a postoperative pulmonary complication during the index hospital stay was an independent risk factor for unplanned 30-day readmission. CONCLUSION: Pediatric patients with American Society of Anesthesiologists classification ≥3 and nutritional deficiency undergoing low-risk surgery are at risk for the development of postoperative complications. Patients who develop wound and postoperative pulmonary complications are at higher risk for unplanned 30-day readmission. Identification of these higher risk patients may allow the anesthesiologist to implement targeted therapies to minimize the likelihood of occurrence of these complications.


Assuntos
Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos Ambulatórios/efeitos adversos , Procedimentos Cirúrgicos Ambulatórios/estatística & dados numéricos , Criança , Bases de Dados Factuais , Feminino , Humanos , Masculino , Readmissão do Paciente , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia
17.
Anesth Analg ; 127(1): 188-189, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29461393

RESUMO

Neuraxial anesthesia has been demonstrated to be safe and effective for children undergoing subumbilical surgery. There is limited evidence regarding the safety of neuraxial anesthesia in pediatric patients with a ventriculoperitoneal shunt. We evaluated a series of 25 patients with indwelling ventriculoperitoneal shunts for complications within 30 days of any procedure performed with a neuraxial technique. One patient required a ventriculoperitoneal shunt revision 5 days after a lumbar catheter placement. The neurosurgeon determined the revision to be likely unrelated to the patient's lumbar catheter. Concerns about the use of neuraxial anesthesia in patients with an indwelling ventriculoperitoneal shunt may be overstated.


Assuntos
Bloqueio Nervoso/métodos , Derivação Ventriculoperitoneal , Catéteres , Criança , Pré-Escolar , Desenho de Equipamento , Falha de Equipamento , Feminino , Humanos , Lactente , Vértebras Lombares , Masculino , Bloqueio Nervoso/efeitos adversos , Bloqueio Nervoso/instrumentação , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Derivação Ventriculoperitoneal/efeitos adversos , Derivação Ventriculoperitoneal/instrumentação
18.
Anesthesiology ; 125(5): 914-928, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27617685

RESUMO

BACKGROUND: To date, the independent predictors and outcomes of unplanned postoperative intubation (UPI) in pediatric patients after noncardiac surgery are yet to be characterized. The authors aimed to identify the incidence and predictors of this event and evaluated the effect of this event on postoperative mortality. METHODS: Data of 87,920 patients from the American College of Surgeons National Surgical Quality Improvement Program Pediatric database were analyzed and assigned to derivation (n = 58,614; 66.7%) or validation (n = 29,306; 33.3%) cohorts. The derivation cohort was analyzed for the incidence and independent predictors of early UPI. The final multivariable logistic regression model was validated using the validation cohort. RESULTS: Early UPI occurred with an incidence of 0.2% in both cohorts. Among the 540 patients who experienced a UPI, 178 (33.0%) were intubated within the first 72 h after surgery. The final logistic regression model indicated operation time, severe cardiac risk factors, American Society of Anesthesiologists physical status classification more than or equal to 2, tumor involving the central nervous system, developmental delay/impaired cognitive function, past or current malignancy, and neonate status as independent predictors of early UPI. Having an early UPI was associated with an increased risk of unadjusted, all-cause 30-day mortality, demonstrating an odds ratio of 11.4 (95% CI, 5.8 to 22.4). CONCLUSIONS: Pediatric patients who experienced an early UPI after noncardiac surgery had an increased likelihood of unadjusted 30-day mortality by more than 11-fold. Identification of high-risk patients can allow for targeted intervention and potential prevention of such outcomes.


Assuntos
Intubação Intratraqueal/estatística & dados numéricos , Cuidados Pós-Operatórios/métodos , Cuidados Pós-Operatórios/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Humanos , Incidência , Tempo de Internação/estatística & dados numéricos , Masculino , Razão de Chances , Estudos Prospectivos , Sistema de Registros , Reprodutibilidade dos Testes , Medição de Risco/estatística & dados numéricos , Fatores de Risco
19.
PLoS One ; 10(3): e0121402, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25747113

RESUMO

PURPOSE: Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD) have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO), the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice. EXPERIMENTAL DESIGN: In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation. RESULTS: Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4), product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice. CONCLUSIONS: This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer.


Assuntos
Hidroxiureia/análogos & derivados , Doenças Inflamatórias Intestinais/prevenção & controle , Polipose Intestinal/prevenção & controle , Inibidores de Lipoxigenase/farmacologia , Animais , Neoplasias do Colo/patologia , Neoplasias do Colo/prevenção & controle , Modelos Animais de Doenças , Feminino , Humanos , Hidroxiureia/farmacologia , Doenças Inflamatórias Intestinais/patologia , Polipose Intestinal/patologia , Masculino , Camundongos , Camundongos Mutantes
20.
Clin Cancer Res ; 19(9): 2342-54, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23487439

RESUMO

PURPOSE: To understand signaling pathways that shape inflamed tissue and predispose to cancer is critical for effective prevention and therapy for chronic inflammatory diseases. We have explored phosphoinositide 3-kinase (PI3K) activity in human inflammatory bowel diseases and mouse colitis models. EXPERIMENTAL DESIGN: We conducted immunostaining of phosphorylated AKT (pAKT) and unbiased high-throughput image acquisition and quantitative analysis of samples of noninflamed normal colon, colitis, dysplasia, and colorectal cancer. Mechanistic insights were gained from ex vivo studies of cell interactions, the piroxicam/IL-10(-/-) mouse model of progressive colitis, and use of the PI3K inhibitor LY294002. RESULTS: Progressive increase in densities of pAKT-positive tumor-associated macrophages (TAM) and increase in densities of mast cells in the colonic submucosa were noted with colitis and progression to dysplasia and cancer. Mast cells recruited macrophages in ex vivo migration assays, and both mast cells and TAMs promoted invasion of cancer cells. Pretreatment of mast cells with LY294002 blocked recruitment of TAMs. LY294002 inhibited mast cell and TAM-mediated tumor invasion, and in mice, blocked stromal PI3K, colitis, and cancer. CONCLUSION: The PI3K/AKT pathway is active in cells infiltrating inflamed human colon tissue. This pathway sustains the recruitment of inflammatory cells through a positive feedback loop. The PI3K/AKT pathway is essential for tumor invasion and the malignant features of the piroxicam/IL-10(-/-) mouse model. LY294002 targets the PI3K pathway and hinders progressive colitis. These findings indicate that colitis and progression to cancer are dependent on stromal PI3K and sensitive to treatment with LY294002.


Assuntos
Colite/imunologia , Neoplasias Colorretais/imunologia , Células Epiteliais/enzimologia , Macrófagos/enzimologia , Mastócitos/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Anticarcinógenos/farmacologia , Degranulação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cromonas/farmacologia , Colite/complicações , Colite/tratamento farmacológico , Colite/patologia , Colo/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Inibidores de Ciclo-Oxigenase/farmacologia , Avaliação Pré-Clínica de Medicamentos , Células HT29 , Humanos , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfolinas/farmacologia , Invasividade Neoplásica , Inibidores de Fosfoinositídeo-3 Quinase , Piroxicam/farmacologia , Transdução de Sinais , Triptases/metabolismo
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