RESUMO
OBJECTIVE: To examine the impact of alvimopan on outcomes and costs in a rigorous enhanced recovery colorectal surgery protocol. BACKGROUND: Postoperative ileus remains a major source of morbidity and costs in colorectal surgery. Alvimopan has been shown to reduce incidence of postoperative ileus in enhanced recovery colorectal surgery; however, data are equivocal regarding its benefit in reducing length of stay and costs. METHODS: Patients undergoing major elective enhanced recovery colorectal surgery were identified from a prospectively-collected database (2010-2013). Multivariable analyses were employed to compare outcomes and hospital costs among patients who had alvimopan versus no alvimopan by adjusting for demographic, clinical, and treatment characteristics. RESULTS: A total of 660 patients were included; 197 patients received alvimopan and 463 patients had no alvimopan. In unadjusted analysis, the alvimopan group had a faster return of bowel function, shorter length of stay, and lower rates of ileus, Foley re-insertion, and urinary tract infection (all Pâ<â0.01). After adjustment, alvimopan was associated with a faster return of bowel function by 0.6 day (Pâ=â0.0006), and lower incidence of postoperative ileus (odds ratio 0.23, Pâ=â0.0002). With adjustment, alvimopan was associated with a shorter length of stay by 1.6 days (Pâ=â0.002), and a hospital cost savings of $1492 per patient (Pâ=â0.01). CONCLUSIONS: Alvimopan administration as an element of enhanced recovery colorectal surgery is associated with faster return of bowel function, lower incidence of postoperative ileus, shorter hospitalization, and a significant cost savings. These results suggest that alvimopan is cost-effective in the setting of enhanced recovery colorectal surgery protocols, and should therefore be considered in these programs.
Assuntos
Cirurgia Colorretal/economia , Redução de Custos/economia , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/economia , Íleus/prevenção & controle , Laparoscopia/economia , Piperidinas/administração & dosagem , Piperidinas/economia , Adulto , Idoso , Índice de Massa Corporal , Análise Custo-Benefício , Feminino , Custos Hospitalares , Humanos , Tempo de Internação/economia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recuperação de Função Fisiológica , Fatores de Risco , Estados UnidosRESUMO
BACKGROUND: Feeding tube placement is common among patients undergoing gastrectomy, and national guidelines currently recommend consideration of a feeding jejunostomy tube (FJT) for all patients undergoing resection for gastric cancer. However, data are limited regarding the safety of FJT placement at the time of gastrectomy for gastric cancer. METHODS: The 2005-2011 American College of Surgeons National Surgical Quality Improvement Program Participant User Files were queried to identify patients who underwent gastrectomy for gastric cancer. Subjects were classified by the concomitant placement of an FJT. Groups were then propensity matched using a 1:1 nearest neighbor algorithm, and outcomes were compared between groups. The primary outcomes of interest were overall 30-d overall complications and mortality. Secondary end points included major complications, surgical site infection, and early reoperation. RESULTS: In total, 2980 subjects underwent gastrectomy for gastric cancer, among whom 715 (24%) also had an FJT placed. Patients who had an FJT placed were more likely to be male (61.6% versus 56.6%, P = 0.02), have recent weight loss (21.0% versus 14.8%, P < 0.01), and have undergone recent chemotherapy (7.9% versus 4.2%, P < 0.01) and radiation therapy (4.2% versus 1.3%, P < 0.01). They were also more likely to have undergone total (compared with partial) gastrectomy (66.6% versus 28.6%, P < 0.01) and have concomitant resection of an adjacent organ (40.4 versus 24.1%, P < 0.01). After adjustment with propensity matching, however, all baseline characteristics and treatment variables were highly similar. Between groups, there were no statistically significant differences in 30-d overall complications (38.8% versus 36.1%, P = 0.32) or mortality (5.8 versus 3.7%, P = 0.08). There were also no differences in major complications, surgical site infection, or early reoperation. Operative time was slightly longer among patients with feeding tubes placed (median, 248 versus 233 min, P = 0.01), but otherwise there were no significant differences in any outcomes between groups. CONCLUSIONS: Concomitant placement of FJT at the time of gastrectomy may result in slightly increased operative times but does not appear to lead to increased perioperative morbidity or mortality. Further investigation is needed to identify the patients most likely to benefit from FJT placement.
Assuntos
Gastrectomia , Jejunostomia/mortalidade , Complicações Pós-Operatórias/etiologia , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Nutrição Enteral/métodos , Feminino , Gastrectomia/mortalidade , Humanos , Intubação Gastrointestinal , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Avaliação de Resultados em Cuidados de Saúde , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias/epidemiologia , Reoperação , Estudos RetrospectivosRESUMO
The outcome of systemic and local therapies (e.g. chemotherapy, radiotherapy, surgery, focal ablation) for prostate cancer can be significantly improved by using tumor-specific adjuvants prior to treatment ("preconditioning"). We propose to use dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to monitor the in vivo response of a mouse model of prostate cancer treated with a vascular disruptive agent, TNF-α, delivered on a gold nanoparticle (NP-TNF). Six male nude mice bearing 4-5 week old LNCaP tumors were scanned at 9.4 T. DCE-MRI was performed two days before and 4-5 h after treatment with NP-TNF. An intraperitoneal (i.p.) bolus of gadolinium-DTPA (Gd) was administered and contrast enhancement was measured for 90 min. Concentration-time curves of Gd were calculated and the area under the Gd curve (AUGC) was determined pre- and post-treatment. NP-TNF treatment caused an increase in contrast uptake in tumors. Interestingly, the early concentration (10 min post Gd bolus i.p.) was similar in both untreated and treated conditions; however, 90 min after injection, [Gd] was 3.4 times higher than before treatment. AUGC doubled from (11 ± 6) [Gd] × min before treatment to (22 ± 9) [Gd] × min after treatment. An increase in signal enhancement was also observed in the muscle but to a lesser degree. We also evaluated the kinetics of intravenous Gd administration in mice bearing a jugular vein catheter to mimic the delivery method used in clinical trials. The overall treatment effects were independent of the delivery pathway of the contrast agent. In conclusion, we show that DCE-MRI is suitable to detect changes associated with a vascular disruptive agent in a mouse model of prostate cancer. The ability to characterize the effects of nanoparticle therapy in vivo with non-destructive methods is important, as such compounds, in combination with treatment strategies, are progressing towards clinical trials.
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Imageamento por Ressonância Magnética/métodos , Nanopartículas/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Fator de Necrose Tumoral alfa/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante/métodos , Meios de Contraste/farmacocinética , Monitoramento de Medicamentos/métodos , Gadolínio DTPA/farmacocinética , Masculino , Camundongos , Camundongos Nus , Nanopartículas/química , Prognóstico , Resultado do TratamentoRESUMO
Surgery, radiation and chemotherapy remain the mainstay of current cancer therapy. However, treatment failure persists due to the inability to achieve complete local control of the tumor and curtail metastatic spread. Vascular disrupting agents (VDAs) are a class of promising systemic agents that are known to synergistically enhance radiation, chemotherapy or thermal treatments of solid tumors. Unfortunately, there is still an unmet need for VDAs with more favorable safety profiles and fewer side effects. Recent work has demonstrated that conjugating VDAs to other molecules (polyethylene glycol, CNGRCG peptide) or nanoparticles (liposomes, gold) can reduce toxicity of one prominent VDA (tumor necrosis factor alpha, TNF-α). In this report, we show the potential of a gold conjugated TNF-α nanoparticle (NP-TNF) to improve multimodal cancer therapies with VDAs. In a dorsal skin fold and hindlimb murine xenograft model of prostate cancer, we found that NP-TNF disrupts endothelial barrier function and induces a significant increase in vascular permeability within the first 1-2 h followed by a dramatic 80% drop in perfusion 2-6 h after systemic administration. We also demonstrate that the tumor response to the nanoparticle can be verified using dynamic contrast-enhanced magnetic resonance imaging (MRI), a technique in clinical use. Additionally, multimodal treatment with thermal therapies at the perfusion nadir in the sub- and supraphysiological temperature regimes increases tumor volumetric destruction by over 60% and leads to significant tumor growth delays compared to thermal therapy alone. Lastly, NP-TNF was found to enhance thermal therapy in the absence of neutrophil recruitment, suggesting that immune/inflammatory regulation is not central to its power as part of a multimodal approach. Our data demonstrate the potential of nanoparticle-conjugated VDAs to significantly improve cancer therapy by preconditioning tumor vasculature to a secondary insult in a targeted manner. We anticipate our work to direct investigations into more potent tumor vasculature specific combinations of VDAs and nanoparticles with the goal of transitioning optimal regimens into clinical trials.
Assuntos
Antineoplásicos/administração & dosagem , Nanoconjugados/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Fator de Necrose Tumoral alfa/administração & dosagem , Animais , Linhagem Celular Tumoral , Terapia Combinada , Ouro , Humanos , Hipertermia Induzida , Masculino , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Camundongos , Camundongos Nus , Nanoconjugados/química , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/terapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: To explore the effects of volume and concentration in thermochemical ablation using an in vivo porcine model. METHODS: Twelve swine 60-75 kg were used in this institutionally approved study. A needle design prototype coaxial device for reagent injections and a thermocouple were inserted into surgically exposed liver. Simultaneously, an acid and base (acetic acid and NaOH) were injected at 4 mL/min based on a 3 × 3 matrix with concentration (5, 10, and 15 mol/L) and volume on the axes (total volumes of 1, 2, and 4 mL). Three animals (centre grid position) strengthened the statistical analysis. Each animal received four identical injections (total 48). Temperatures and heart rate were recorded. Livers were formalin-fixed after sacrifice. After sectioning, coagulation zones were analysed by two observers. Area and slice thickness were used to calculate the volume, surface area, and sphericity for each treatment. RESULTS: Coagulation volumes ranged from 2.95 ± 0.29 to 14.72 ± 1.42 mL with a maximum of 18.3 mL. Highest peak temperature was 105°C with temperatures ranging 43.5 ± 2.6°C to 91.0 ± 6.5°C. There was no association between conditions and sphericity or heart rate. CONCLUSIONS: The method can be used successfully to ablate tissue in vivo. By neutralising acid in situ and releasing heat and a salt, this technique improves considerably upon the use of acetic acid used alone. Peak temperatures exceeded accepted coagulation thresholds even if the only mechanism operating was hyperthermia. Reagent concentrations and volumes increased the amount of the coagulum but not in a linear fashion.
Assuntos
Técnicas de Ablação/métodos , Temperatura Alta/uso terapêutico , Hipertermia Induzida/métodos , Técnicas de Ablação/instrumentação , Ácido Acético/química , Ácido Acético/uso terapêutico , Animais , Hipertermia Induzida/instrumentação , Fígado/patologia , Fígado/cirurgia , Modelos Animais , Necrose , Hidróxido de Sódio/química , Hidróxido de Sódio/uso terapêutico , SuínosRESUMO
PURPOSE: To investigate simultaneous and sequential injection thermochemical ablation in a porcine model, and compare them to sham and acid-only ablation. MATERIALS AND METHODS: This IACUC-approved study involved 11 pigs in an acute setting. Ultrasound was used to guide placement of a thermocouple probe and coaxial device designed for thermochemical ablation. Solutions of 10 M acetic acid and NaOH were used in the study. Four injections per pig were performed in identical order at a total rate of 4 mL/min: saline sham, simultaneous, sequential, and acid only. Volume and sphericity of zones of coagulation were measured. Fixed specimens were examined by H&E stain. RESULTS: Average coagulation volumes were 11.2 mL (simultaneous), 19.0 mL (sequential) and 4.4 mL (acid). The highest temperature, 81.3°C, was obtained with simultaneous injection. Average temperatures were 61.1°C (simultaneous), 47.7°C (sequential) and 39.5°C (acid only). Sphericity coefficients (0.83-0.89) had no statistically significant difference among conditions. CONCLUSIONS: Thermochemical ablation produced substantial volumes of coagulated tissues relative to the amounts of reagents injected, considerably greater than acid alone in either technique employed. The largest volumes were obtained with sequential injection, yet this came at a price in one case of cardiac arrest. Simultaneous injection yielded the highest recorded temperatures and may be tolerated as well as or better than acid injection alone. Although this pilot study did not show a clear advantage for either sequential or simultaneous methods, the results indicate that thermochemical ablation is attractive for further investigation with regard to both safety and efficacy.
Assuntos
Técnicas de Ablação/métodos , Temperatura Alta/uso terapêutico , Fígado/cirurgia , Técnicas de Ablação/instrumentação , Ácido Acético/administração & dosagem , Animais , Hipertermia Induzida/métodos , Fígado/patologia , Modelos Animais , Suínos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Our study aims to identify the minimum number of lymph nodes (LN) associated with improved survival in patients who underwent NRT for stage II-III rectal cancer. METHODS: Adults with clinical stage II and III rectal adenocarcinoma in the National Cancer Data Base were stratified by NRT. Multivariable Cox regression modeling with restricted cubic splines was used to determine the minimum number of LNs associated with improved survival. RESULTS: Of 38,363 patients, 76% received NRT. After adjustment, a LNY≥12 was associated with improved survival among patients receiving NRT (HR 0.79, p < 0.0001) and those without NRT (HR 0.88, p = 0.04). Among patients receiving NRT, factors independently associated with LNY≥12 were younger age, private insurance, low comorbidity score, a recent year of diagnosis, higher T stage and grade, APR resection, and academic institution. CONCLUSIONS: A minimum LNY of 12 confers a survival benefit for rectal cancer patients regardless of receiving neoadjuvant radiation therapy.
Assuntos
Adenocarcinoma/terapia , Colectomia/métodos , Linfonodos/patologia , Estadiamento de Neoplasias , Neoplasias Retais/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/secundário , Idoso , Quimiorradioterapia Adjuvante , Feminino , Seguimentos , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Retais/diagnóstico , Neoplasias Retais/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) has demonstrated proven benefit in tumor regression and improved long-term local control for patients with locally advanced rectal cancer. However, precise analysis of the optimal waiting time that maximizes oncologic benefits of nCRT has not been established. STUDY DESIGN: The 2006-2012 National Cancer Data Base was queried for patients with stage II and III rectal adenocarcinoma who underwent nCRT followed by surgical resection. Time to surgery was defined as the difference between last date of radiotherapy and date of surgery. Primary study endpoints included resection margin positivity and pathologic downstaging. Multivariable regression modeling with restricted cubic splines was used to evaluate the adjusted association between time to surgery and our study endpoints, and to establish an optimal time threshold for surgery. RESULTS: A total of 11,760 patients were included. Median time to surgery was 53 days (interquartile range [IQR] 43 to 63 days). After adjusting for patient demographic, clinical, tumor, and treatment characteristics, our model determined an inflection point at 56 days after end of radiotherapy associated with the highest likelihood of complete resection and pathologic downstaging. With adjustment, the risk of margin positivity was increased in those who underwent surgery after 56 days from end of radiotherapy (odds ratio [OR] 1.40, 95% CI 1.21 to 1.61, p < 0.001). The likelihood of downstaging was increasing up to 56 days after radiotherapy (≥56 days vs <56 days, OR 1.2, 95% CI 1.02 to 1.23, p = 0.01). CONCLUSIONS: This study objectively determined the optimal time for surgery after completion of nCRT for rectal cancer based on completeness of resection and tumor downstaging. Eight weeks appears to be the critical threshold for optimal tumor response.
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Adenocarcinoma/terapia , Quimiorradioterapia , Terapia Neoadjuvante , Neoplasias Retais/terapia , Tempo para o Tratamento , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Estudos de Coortes , Feminino , Hospitalização , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
Nanoparticles show tremendous promise in the safe and effective delivery of molecular adjuvants to enhance local cancer therapy. One important form of local cancer treatment that suffers from local recurrence and distant metastases is thermal therapy. In this article, we review a new concept involving the use of nanoparticle-delivered adjuvants to 'precondition' or alter the vascular and immunological biology of the tumor to enhance its susceptibility to thermal therapy. To this end, a number of opportunities to combine nanoparticles with vascular and immunologically active agents are reviewed. One specific example of preconditioning involves a gold nanoparticle tagged with a vascular targeting agent (i.e., TNF-α). This nanoparticle embodiment demonstrates preconditioning through a dramatic reduction in tumor blood flow and induction of vascular damage, which recruits a strong and sustained inflammatory infiltrate in the tumor. The ability of this nanoparticle preconditioning to enhance subsequent heat or cold thermal therapy in a variety of tumor models is reviewed. Finally, the potential for future clinical imaging to judge the extent of preconditioning and thus the optimal timing and extent of combinatorial thermal therapy is discussed.
Assuntos
Hipertermia Induzida/métodos , Nanopartículas/química , Neoplasias/terapia , Adjuvantes Farmacêuticos , Animais , Criocirurgia , Crioterapia , Coloide de Ouro/química , Humanos , Camundongos , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
OBJECTIVES: Radiofrequency ablation (RFA) has been most effective when the tumors are small, exophytic, and away from vital structures. We enlarged the size of the ablation kill zone by infusing a 30-nm tumor necrosis factor-alpha and polyethylene glycol-coated gold nanoparticle (CYT-6091, CytImmune Sciences, Inc.) before ablation in a rabbit kidney tumor model. MATERIALS AND METHODS: A total of 37 New Zealand White rabbits had VX-2 tumors implanted into their bilateral kidneys; they were then split into 3 treatment groups of 10 rabbits each and a sham group of 7 rabbits as follows: (1) CYT-6091 only, (2) RFA only, (3) CYT-6091 followed 4 hours later by RFA. Gross and microscopic measurements of the ablation size as well as histologic analysis using hematoxylin and eosin staining were performed to determine the effect of CYT-6091 on the ablation. RESULTS: The RFA + CYT-6091 group had a larger zone of complete cell death than the RFA-only group when measured on microscopic examination (0.30 +/- 0.07 vs 0.23 +/- 0.03 mL, P = .03). The zone of partially ablated tissue was smaller in the RFA + CYT-6091 group than in the RFA-only group (0.08 +/- 0.02 vs 0.13 +/- 0.05 mL, P = .01). CONCLUSIONS: We have demonstrated the efficacy of CYT-6091 in enhancing RFA in a translational kidney tumor model. The potential usage of CYT-6091 to improve RFA of renal cell carcinoma merits further study.
Assuntos
Ablação por Cateter/métodos , Modelos Animais de Doenças , Neoplasias Renais/cirurgia , Nanopartículas Metálicas , Fator de Necrose Tumoral alfa/administração & dosagem , Animais , Feminino , Ouro , CoelhosRESUMO
Applications involving freeze-thaw, such as cryoplasty or cryopreservation can significantly alter artery biomechanics including an increase in physiological elastic modulus. Since artery biomechanics plays a significant role in hemodynamics, it is important to understand the mechanisms underlying these changes to be able to help control the biomechanical outcome post-treatments. Understanding of these mechanisms requires investigation of the freeze-thaw effect on arterial components (collagen, smooth muscle cells or SMCs), as well as the components' contribution to the overall artery biomechanics. To do this, isolated fresh swine arteries were subjected to thermal (freeze-thaw to -20 degrees C for 2 min or hyperthermia to 43 degrees C for 2 h) and osmotic (0.1-0.2 M mannitol) treatments; these treatments preferentially altered either the collagen matrix (hydration/stability) or smooth muscle cells (SMCs), respectively. Tissue dehydration, thermal stability and SMC functional changes were assessed from bulk weight measurements, analyses of the thermal denaturation profiles using Fourier transform infrared (FTIR) spectroscopy and in vitro arterial contraction/relaxation responses to norepinephrine (NE) and acetylcholine (AC), respectively. Additionally, Second Harmonic Generation (SHG) microscopy was performed on fresh and frozen-thawed arteries to directly visualize the changes in collagen matrix following freeze-thaw. Finally, the overall artery biomechanics was studied by assessing responses to uniaxial tensile testing. Freeze-thaw of arteries caused: (a) tissue dehydration (15% weight reduction), (b) increase in thermal stability (approximately 6.4 degrees C increase in denaturation onset temperature), (c) altered matrix arrangement observed using SHG and d) complete SMC destruction. While hyperthermia treatment also caused complete SMC destruction, no tissue dehydration was observed. On the other hand, while 0.2 M mannitol treatment significantly increased the thermal stability (approximately 4.8 degrees C increase in denaturation onset), 0.1 M mannitol treatment did not result in any significant change. Both 0.1 and 0.2 M treatments caused no change in SMC function. Finally, freeze-thaw (506+/-159 kPa), hyperthermia (268+/-132 kPa) and 0.2 M mannitol (304+/-125 kPa) treatments all caused significant increase in the physiological elastic modulus (Eartery) compared to control (185+/-92 kPa) with the freeze-thaw resulting in the highest modulus. These studies suggest that changes in collagen matrix arrangement due to dehydration as well as SMC destruction occurring during freeze-thaw are important mechanisms of freeze-thaw induced biomechanical changes.
Assuntos
Artérias/fisiologia , Colágeno/fisiologia , Matriz Extracelular/fisiologia , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/fisiologia , Adaptação Fisiológica/fisiologia , Animais , Apoptose/fisiologia , Células Cultivadas , Módulo de Elasticidade/fisiologia , Congelamento , Temperatura Alta , Técnicas In Vitro , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Estresse Mecânico , SuínosRESUMO
Thermal therapies such as hyperthermia, radiofrequency ablation, cryoablation, etc. have shown great potential and are gaining increasing clinical acceptance in the treatment of solid tumors. However, these treatment modalities are limited by the size of tumor that can be treated, incomplete tumor kill, and damage to adjacent normal tissues. To address these limitations, the concept of adjuvant-assisted thermal therapies has been proposed and tested to enhance the tumor destructive effects of thermal therapies. CYT-6091, a pegylated colloidal gold nanoparticle containing TNF-alpha bound to its surface, has been extensively investigated in our lab as an adjuvant to enhance thermal therapies. This paper describes our investigations of nanoparticle enhanced thermal therapies in various preclinical and translational models of solid tumors.