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1.
HPB (Oxford) ; 24(4): 558-567, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34629261

RESUMO

BACKGROUND: The aim of this survey was to assess practices regarding pain management, fluid therapy and thromboprophylaxis in patients undergoing pancreatoduodenectomy on a global basis. METHODS: This survey study among surgeons from eight (inter)national scientific societies was performed according to the CHERRIES guideline. RESULTS: Overall, 236 surgeons completed the survey. ERAS protocols are used by 61% of surgeons and respectively 82%, 93%, 57% believed there is a relationship between pain management, fluid therapy, and thromboprophylaxis and clinical outcomes. Epidural analgesia (50%) was most popular followed by intravenous morphine (24%). A restrictive fluid therapy was used by 58% of surgeons. Chemical thromboprophylaxis was used by 88% of surgeons. Variations were observed between continents, most interesting being the choice for analgesic technique (transversus abdominis plane block was popular in North America), restrictive fluid therapy (little use in Asia and Oceania) and duration of chemical thromboprophylaxis (large variation). CONCLUSION: The results of this international survey showed that only 61% of surgeons practice ERAS protocols. Although the majority of surgeons presume a relationship between pain management, fluid therapy and thromboprophylaxis and clinical outcomes, variations in practices were observed. Additional studies are needed to further optimize, standardize and implement ERAS protocols after pancreatic surgery.


Assuntos
Cirurgiões , Tromboembolia Venosa , Analgésicos Opioides/uso terapêutico , Anticoagulantes/efeitos adversos , Hidratação/efeitos adversos , Humanos , Manejo da Dor/métodos , Dor Pós-Operatória/prevenção & controle , Pancreaticoduodenectomia/efeitos adversos , Tromboembolia Venosa/prevenção & controle
2.
Ann Med Surg (Lond) ; 54: 37-42, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32368338

RESUMO

BACKGROUND: Colonic resection is a common surgical procedure associated with a high rate of postoperative complications. The aim of this observational study is to estimate the in-hospital costs of complications and to identify perioperative variables associated with complication development following colon resection surgery. MATERIALS AND METHODS: We conducted a single-centre cohort study with retrospective data collection of 487 patients undergoing colonic resection surgery between 2013 and 2018. Postoperative complications were graded according to the Clavien-Dindo classification system. In-hospital cost of index admission is reported in 2019 United States Dollars. Regression modelling was used to investigate the relationship of a priori selected perioperative variables and presence of complications and costs. RESULTS: Overall complication prevalence was 69.6% (95%CI:65.5%-73.7%). Median [interquartile range] cost of patients with postoperative complications was significantly increased as compared to patients without complications ($17,963 [13,533:25,178] vs $12,578 [10,196:16,140]; p < 0.0001). Clavien-Dindo Grade I, II, III and IV complications increased costs by 15.8%, 36.8%, 169.4% and 240.1% respectively (p < 0.0001). Presence of complications was significantly associated with Charlson Comorbidity Index (Odds ratio (OR) per 1-unit increase: 1.09; 95%CI:1.02 to 1.17), preoperative albumin levels (OR per 1-unit increase: 0.94; 95%CI:0.90 to 0.98) and open as compared to laparoscopic resection (OR: 2.41; 95%CI:1.32 to 4.42). CONCLUSIONS: There is a high prevalence of complications following colonic resection surgery. Postoperative complications, including minor complications (Clavien-Dindo Grade I-II), were associated with a significant increase in hospital costs and are a key target for cost containment strategies.

3.
BMC Anesthesiol ; 19(1): 135, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366327

RESUMO

BACKGROUND: Right hepatectomy is a complex procedure that carries inherent risks of perioperative morbidity. To evaluate outcome differences between a low central venous pressure fluid intervention strategy and a goal directed fluid therapy (GDFT) cardiac output algorithm we performed a retrospective observational study. We hypothesized that a GDFT protocol would result in less intraoperative fluid administration, reduced complications and a shorter length of hospital stay. METHODS: Patients undergoing hepatectomy using an established enhanced recovery after surgery (ERAS) programme between 2010 and 2017 were extracted from a prospectively managed electronic hospital database. Inclusion criteria included adult patients, undergoing open right (segments V-VIII) or extended right (segments IV-VIII) hepatectomy. PRIMARY OUTCOME: amount of intraoperative fluid administration used between the two groups. SECONDARY OUTCOMES: type and amount of vasoactive medications used, the development of predefined postoperative complications, hospital length of stay, and 30-day mortality. Complications were defined by the European Perioperative Clinical Outcome definitions and graded according to Clavien-Dindo classification. The association between GDFT and the amount of fluid and vasoactive medication used was investigated using logistic and linear regression models. RESULTS: Fifty-eight consecutive patients were identified. 26 patients received GDFT and 32 received Usual care. There were no significant differences in baseline patient characteristics. Less intraoperative fluid was used in the GDFT group: median (IQR) 2000 ml (1175 to 2700) vs. 2750 ml (2000 to 4000) in the Usual care group; p = 0.03. There were no significant differences in the use of vasoactive medications. Postoperative complications were similar: 9 patients (35%) in the GDFT group vs. 18 patients (56%) in the Usual care group; p = 0.10, OR: 0.41; (95%CI: 0.14 to 1.20). Median (IQR) length of stay for patients in the GDFT group was 7 days (6:8) vs. 9 days (7:13) in the Usual care group; incident rate ratio 0.72 (95%CI: 0.56 to 0.93); p = 0.012. There was no difference in perioperative mortality. CONCLUSIONS: In patients undergoing open right hepatectomy with an established ERAS programme, use of GDFT was associated with less intraoperative fluid administration and reduced hospital length of stay when compared to Usual care. There were no significant differences in postoperative complications or mortality. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: no 12619000558123 on 10/4/19.


Assuntos
Algoritmos , Protocolos Clínicos , Hidratação/métodos , Hepatectomia , Idoso , Débito Cardíaco , Pressão Venosa Central , Recuperação Pós-Cirúrgica Melhorada , Feminino , Hidratação/estatística & dados numéricos , Humanos , Cuidados Intraoperatórios , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Retrospectivos , Vasoconstritores/uso terapêutico
4.
Ann Med Surg (Lond) ; 45: 45-53, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31360460

RESUMO

BACKGROUND: The effect a restrictive goal directed therapy (GDT) fluid protocol combined with an enhanced recovery after surgery (ERAS) programme on hospital stay for patients undergoing major liver resection is unknown. METHODS: We conducted a multicentre randomized controlled pilot trial evaluating whether a patient-specific, surgery-specific intraoperative restrictive fluid optimization algorithm would improve duration of hospital stay and reduce perioperative fluid related complications. RESULTS: Forty-eight participants were enrolled. The median (IQR) length of hospital stay was 7.0 days (7.0:8.0) days in the restrictive fluid optimization algorithm group (Restrict group) vs. 8.0 days (6.0:10.0) in the conventional care group (Conventional group) (Incidence rate ratio 0.85; 95% Confidence Interval 0.71:1.1; p = 0.17). No statistically significant difference in expected number of complications per patient between groups was identified (IRR 0.85; 95%CI: 0.45-1.60; p = 0.60). Patients in the Restrict group had lower intraoperative fluid balances: 808 mL (571:1565) vs. 1345 mL (900:1983) (p = 0.04) and received a lower volume of fluid per kg/hour intraoperatively: 4.3 mL/kg/hr (2.6:5.8) vs. 6.0 mL/kg/hr (4.2:7.6); p = 0.03. No significant differences in the proportion of patients who received vasoactive drugs intraoperatively (p = 0.56) was observed. CONCLUSION: In high-volume hepatobiliary surgical units, the addition of a fluid restrictive intraoperative cardiac output-guided algorithm, combined with a standard ERAS protocol did not significantly reduce length of hospital stay or fluid related complications. Our findings are hypothesis-generating and a larger confirmatory study may be justified.

5.
ANZ J Surg ; 88(12): 1337-1342, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30414227

RESUMO

BACKGROUND: Acute biliary pain is the most common presentation of gallstone disease. Untreated patients risk recurrent pain, cholecystitis, obstructive jaundice, pancreatitis and multiple hospital presentations. We examine the outcome of implementing a policy to offer laparoscopic cholecystectomy on index presentation to patients with biliary colic in a tertiary hospital in Australia. METHODS: This is a retrospective cohort study of adult patients presenting to the emergency department (ED) with biliary pain during three 12-month periods. Outcomes in Group A, 3 years prior to policy implementation, were compared with groups 2 and 7 years post implementation (Groups B and C). Primary outcomes were representations to ED, admission rate and time to cholecystectomy. RESULTS: A total of 584 patients presented with biliary colic during the three study periods. Of these, 391 underwent cholecystectomy with three Strasberg Type A bile leaks and no bile duct injuries. The policy increased admission rates (A = 15.8%, B = 62.9%, C = 29.5%, P < 0.001) and surgery on index presentation (A = 12.0%, B = 60.7%, C = 27.4%, P < 0.001). There was a decline in time to cholecystectomy (days) (A = 143, B = 15, C = 31, P < 0.001), post-operative length of stay (days) (A = 3.6, B = 3.2, C = 2.0, P < 0.05) and representation rates to ED (A = 42.1%, B = 7.1%, C = 19.9%, P < 0.001). There was a decline in policy adherence in the later cohort. CONCLUSION: Index hospital admission and cholecystectomy for biliary colic decrease patient representations, time to surgery, post-operative stay and complications of gallstone disease. This study demonstrates the impact of the policy with initial improvement, the dangers of policy attrition and the need for continued reinforcement.


Assuntos
Dor Abdominal/diagnóstico , Dor Aguda/diagnóstico , Doenças Biliares/complicações , Colecistectomia Laparoscópica/métodos , Gerenciamento Clínico , Emergências , Centros de Atenção Terciária , Dor Abdominal/etiologia , Dor Abdominal/cirurgia , Dor Aguda/etiologia , Dor Aguda/cirurgia , Adulto , Doenças Biliares/diagnóstico , Doenças Biliares/cirurgia , Serviços Médicos de Emergência , Feminino , Seguimentos , Humanos , Tempo de Internação/tendências , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Vitória
6.
N Engl J Med ; 378(24): 2263-2274, 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29742967

RESUMO

BACKGROUND: Guidelines to promote the early recovery of patients undergoing major surgery recommend a restrictive intravenous-fluid strategy for abdominal surgery. However, the supporting evidence is limited, and there is concern about impaired organ perfusion. METHODS: In a pragmatic, international trial, we randomly assigned 3000 patients who had an increased risk of complications while undergoing major abdominal surgery to receive a restrictive or liberal intravenous-fluid regimen during and up to 24 hours after surgery. The primary outcome was disability-free survival at 1 year. Key secondary outcomes were acute kidney injury at 30 days, renal-replacement therapy at 90 days, and a composite of septic complications, surgical-site infection, or death. RESULTS: During and up to 24 hours after surgery, 1490 patients in the restrictive fluid group had a median intravenous-fluid intake of 3.7 liters (interquartile range, 2.9 to 4.9), as compared with 6.1 liters (interquartile range, 5.0 to 7.4) in 1493 patients in the liberal fluid group (P<0.001). The rate of disability-free survival at 1 year was 81.9% in the restrictive fluid group and 82.3% in the liberal fluid group (hazard ratio for death or disability, 1.05; 95% confidence interval, 0.88 to 1.24; P=0.61). The rate of acute kidney injury was 8.6% in the restrictive fluid group and 5.0% in the liberal fluid group (P<0.001). The rate of septic complications or death was 21.8% in the restrictive fluid group and 19.8% in the liberal fluid group (P=0.19); rates of surgical-site infection (16.5% vs. 13.6%, P=0.02) and renal-replacement therapy (0.9% vs. 0.3%, P=0.048) were higher in the restrictive fluid group, but the between-group difference was not significant after adjustment for multiple testing. CONCLUSIONS: Among patients at increased risk for complications during major abdominal surgery, a restrictive fluid regimen was not associated with a higher rate of disability-free survival than a liberal fluid regimen and was associated with a higher rate of acute kidney injury. (Funded by the Australian National Health and Medical Research Council and others; RELIEF ClinicalTrials.gov number, NCT01424150 .).


Assuntos
Abdome/cirurgia , Injúria Renal Aguda/etiologia , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Hidratação/métodos , Complicações Pós-Operatórias/prevenção & controle , Soluções para Reidratação/administração & dosagem , Idoso , Perda Sanguínea Cirúrgica , Procedimentos Cirúrgicos do Sistema Digestório/mortalidade , Feminino , Hidratação/efeitos adversos , Seguimentos , Humanos , Soluções Hipotônicas/administração & dosagem , Soluções Hipotônicas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Soluções para Reidratação/efeitos adversos , Soluções para Reidratação/química , Fatores de Risco
7.
PLoS One ; 12(9): e0183313, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28880931

RESUMO

We aimed to evaluate perioperative outcomes in patients undergoing pancreaticoduodenectomy with or without a cardiac output goal directed therapy (GDT) algorithm. We conducted a multicentre randomised controlled trial in four high volume hepatobiliary-pancreatic surgery centres. We evaluated whether the additional impact of a intraoperative fluid optimisation algorithm would influence the amount of fluid delivered, reduce fluid related complications, and improve length of hospital stay. Fifty-two consecutive adult patients were recruited. The median (IQR) duration of surgery was 8.6 hours (7.1:9.6) in the GDT group vs. 7.8 hours (6.8:9.0) in the usual care group (p = 0.2). Intraoperative fluid balance was 1005mL (475:1873) in the GDT group vs. 3300mL (2474:3874) in the usual care group (p<0.0001). Total volume of fluid administered intraoperatively was also lower in the GDT group: 2050mL (1313:2700) vs. 4088mL (3400:4525), p<0.0001 and vasoactive medications were used more frequently. There were no significant differences in proportions of patients experiencing overall complications (p = 0.179); however, fewer complications occurred in the GDT group: 44 vs. 92 (Incidence Rate Ratio: 0.41; 95%CI 0.24 to 0.69, p = 0.001). Median (IQR) length of hospital stay was 9.5 days (IQR: 7.0, 14.3) in the GDT vs. 12.5 days in the usual care group (IQR: 9.0, 22.3) for an Incidence Rate Ratio 0.64 (95% CI 0.48 to 0.85, p = 0.002). In conclusion, using a surgery-specific, patient-specific goal directed restrictive fluid therapy algorithm in this cohort of patients, can justify using enough fluid without causing oedema, yet as little fluid as possible without causing hypovolaemia i.e. "precision" fluid therapy. Our findings support the use of a perioperative haemodynamic optimization plan that prioritizes preservation of cardiac output and organ perfusion pressure by judicious use of fluid therapy, rational use of vasoactive drugs and timely application of inotropic drugs. They also suggest the need for further larger studies to confirm its findings.


Assuntos
Algoritmos , Hidratação/métodos , Pancreaticoduodenectomia/métodos , Idoso , Débito Cardíaco/fisiologia , Feminino , Hemodinâmica/fisiologia , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Volume Sistólico/fisiologia , Resultado do Tratamento
8.
BMJ Open ; 7(3): e015358, 2017 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-28259855

RESUMO

INTRODUCTION: The optimal intravenous fluid regimen for patients undergoing major abdominal surgery is unclear. However, results from many small studies suggest a restrictive regimen may lead to better outcomes. A large, definitive clinical trial evaluating perioperative fluid replacement in major abdominal surgery, therefore, is required. METHODS/ANALYSIS: We designed a pragmatic, multicentre, randomised, controlled trial (the RELIEF trial). A total of 3000 patients were enrolled in this study and randomly allocated to a restrictive or liberal fluid regimen in a 1:1 ratio, stratified by centre and planned critical care admission. The expected fluid volumes in the first 24 hour from the start of surgery in restrictive and liberal groups were ≤3.0 L and ≥5.4 L, respectively. Patient enrolment is complete, and follow-up for the primary end point is ongoing. The primary outcome is disability-free survival at 1 year after surgery, with disability defined as a persistent (at least 6 months) reduction in functional status using the 12-item version of the World Health Organisation Disability Assessment Schedule. ETHICS/DISSEMINATION: The RELIEF trial has been approved by the responsible ethics committees of all participating sites. Participant recruitment began in March 2013 and was completed in August 2016, and 1-year follow-up will conclude in August 2017. Publication of the results of the RELIEF trial is anticipated in early 2018. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT01424150.


Assuntos
Abdome/cirurgia , Hidratação/métodos , Complicações Pós-Operatórias/prevenção & controle , Projetos de Pesquisa , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
9.
ANZ J Surg ; 86(11): 868-873, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27302217

RESUMO

Hepatic malignancy with regional lymph node involvement is generally associated with poor prognosis. Lymphatic drainage from the liver to extrahepatic lymph nodes follows a complex and unpredictable pathway. To add to the complexity of management of regional lymph nodes in hepatic malignancies, not all liver cancers have the same propensity to metastasize through lymphatics. Lymphadenectomy has had mixed results in terms of improving patient survival. Other therapies especially anti-lymphogenic agents might play a role in the near future.


Assuntos
Neoplasias Hepáticas , Vasos Linfáticos/anatomia & histologia , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Metástase Linfática
10.
Surgery ; 158(1): 236-47, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25999256

RESUMO

BACKGROUND: Pirarubicin, a derivative of doxorubicin, induces tumor destruction via the production of reactive oxygen species (ROS) but is associated with cardiotoxicity. As a macromolecule (conjugated to styrene-maleic acid [SMA]), SMA-pirarubicin is selective to tumors resulting in improved survival with decreased systemic toxicity. Tumor destruction is, however incomplete, and resistant cells at the periphery of the tumor contribute to recurrence. Tumor hypoxia is a major factor in tumor resistance. Understanding the effect of oxidative stress induced by SMA-pirarubicin on the tumor microenvironment may be key to overcoming resistance. This study investigated the pattern of ROS production and tumor hypoxia after treatment with SMA-pirarubicin in a murine model of colorectal liver metastases. METHODS: Liver metastases were induced in male, CBA mice using a murine-derived colon cancer cell line. SMA-pirarubicin (maximum tolerated dose, 100 mg/kg) or pirarubicin, (maximum tolerated dose, 10 mg/kg) were administered intravenously 14 days after tumor induction. Systemic oxidative stress in serum, liver, and cardiac tissue was quantified using the thiobarbituric acid reactive substances assay. Flow cytometry and fluorescence microscopy were used to assess ROS production for 48 hours after treatment. Tumor hypoxia was quantified using immunohistochemistry for pimonidazole adducts. RESULTS: SMA-pirarubicin (100 mg/kg) induced ROS exclusively in tumors with minimal levels in serum and cardiac tissue. ROS levels were induced in a time-dependent and dose-dependent manner optimal between 4 and 24 hours after drug administration. Although tumor hypoxia was decreased overall, residual tumor cells adjacent to patent vessels were hypoxic. CONCLUSION: This study provides insight into the tumor microenvironment after chemotherapy. SMA-pirarubicin inhibits the growth of colorectal liver metastases by inducing ROS, which seems to be largely tumor selective. The temporal pattern of ROS production can be used to improve future dosing regimens. Furthermore, the observation that residual tumor cells are hypoxic clarifies the need for a multimodal approach with agents that can alter the hypoxic state to effect complete tumor destruction.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Hipóxia Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Masculino , Maleatos/administração & dosagem , Camundongos , Camundongos Endogâmicos CBA , Poliestirenos/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos
11.
Surgeon ; 8(4): 223-31, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20569943

RESUMO

Splenic artery aneurysm is the third most common intra-abdominal aneurysm with a prevalence as high as 10% in some studies. Widespread use of abdominal imaging has resulted in the increasing detection of asymptomatic incidental aneurysms. In this manuscript we review the changing incidence, risk factors and evolving therapeutic options in the era of minimally invasive therapy and have developed a treatment algorithm for practical use. Aneurysms with a low risk of rupture may be treated conservatively but require regular imaging to ascertain progress. Available evidence suggests that splenic artery aneurysms that are symptomatic, enlarging, more than 2 cm in diameter or those detected in pregnancy, childbearing age or following liver transplantation are at high risk of rupture and should undergo active treatment. Prophylactic screening should be reserved for those with multiple risk factors, such as pregnancy in liver transplant recipients. All false aneurysms should also be treated. The primary therapeutic approach should be endovascular therapy by either embolization or stent grafting.


Assuntos
Aneurisma/terapia , Artéria Esplênica , Algoritmos , Aneurisma/diagnóstico , Falso Aneurisma/diagnóstico , Falso Aneurisma/terapia , Diagnóstico por Imagem , Feminino , Humanos , Incidência , Transplante de Fígado/efeitos adversos , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/terapia , Fatores de Risco
12.
Cancer Sci ; 101(8): 1866-74, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20579075

RESUMO

Pirarubicin is a derivative of doxorubicin with improved intracellular uptake and reduced cardiotoxicity. We have prepared a micellar formulation of pirarubicin using styrene-maleic acid copolymer (SMA) of mean molecular weight of 1.2 kDa, which exhibits a mean diameter of 248 nm in solution. Being a macromolecule, SMA-pirarubicin micelles exhibit excellent tumor targeting capacity due to the enhanced permeability and retention (EPR) effect. Here we report the antitumor activity of SMA-pirarubicin micelles on human colon and breast cancer cell lines in vitro, and a murine liver metastasis model in vivo. Metastatic tumor microvasculature, necrosis, apoptosis, proliferation, and survival were also investigated using immunohistochemistry for Ki-67, active caspase-3, and CD34, respectively. Drug cytotoxicity in vitro was assessed using MTT (3-[4,5-dimethyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromide) assay. In vivo, SMA-pirarubicin was administered at 100, 150, or 200 mg/kg (pirarubicin equivalent). Tumor microvasculature was also assessed using scanning electron microscopy. Styrene-maleic acid copolymer (SMA)-pirarubicin micelles were toxic against human colorectal and breast cancer cells in vitro. IC(50) was at or below 1 muM, free pirarubicin equivalent. In vivo, SMA-pirarubicin at 100 mg/kg reduced tumor volume by 80% and achieved a survival rate of 93% at 40 days after tumor inoculation. Styrene-maleic acid copolymer (SMA)-pirarubicin micelles demonstrated potent antitumor activity in this liver metastases model, contributing to prolonged survival. Histological examination of tumor nodules showed significant reduction and proliferation of tumor cells (>90%). The present results suggest that investigation of the effect of multiple dosing at later time points to further improve survival is warranted.


Assuntos
Doxorrubicina/análogos & derivados , Neoplasias Hepáticas Experimentais/prevenção & controle , Neoplasias Hepáticas Experimentais/secundário , Maleatos/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Poliestirenos/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Caspase 3/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Humanos , Masculino , Camundongos , Camundongos Endogâmicos CBA , Micelas , Necrose , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/mortalidade , Neoplasias Experimentais/patologia
13.
J Vasc Res ; 46(3): 218-28, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-18953175

RESUMO

BACKGROUND: Doxorubicin is a commonly used chemotherapy limited by cardiotoxicity. Pirarubicin, derived from doxorubicin, selectively targets tumors when encapsulated in styrene maleic acid (SMA), forming the macromolecular SMA pirarubicin. Selective targeting is achieved because of the enhanced permeability and retention (EPR) effect. SMA-pirarubicin inhibits the growth of colorectal liver metastases, but tumor destruction is incomplete. The role played by the tumor microcirculation is uncertain. This study investigates the pattern of microcirculatory changes following SMA-pirarubicin treatment. METHODS: Liver metastases were induced in CBA mice using a murine-derived colon cancer line. SMA-pirarubicin (100 mg/kg total dose) was administered intravenously in 3 separate doses. Twenty-four hours after chemotherapy, the tumor microvasculature was examined using CD34 immunohistochemistry and scanning electron microscopy. Tumor perfusion and permeability were assessed using confocal in vivo microscopy and the Evans blue method. RESULTS: SMA-pirarubicin reduced the microvascular index by 40%. Vascular occlusion and necrosis were extensive following treatment. Viable cells were arranged around tumor vessels. Tumor permeability was also increased. CONCLUSION: SMA-pirarubicin damages tumor cells and the tumor microvasculature and enhances tumor vessel permeability. However, tumor necrosis is incomplete, and the growth of residual cells is sustained by a microvascular network. Combined therapy with a vascular targeting agent may affect residual cells, allowing more extensive destruction of tumors.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/análogos & derivados , Neoplasias Hepáticas Experimentais/secundário , Maleatos/administração & dosagem , Estireno/administração & dosagem , Animais , Antígenos CD34/análise , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos CBA , Microcirculação/efeitos dos fármacos , Microscopia Confocal , Necrose , Permeabilidade
14.
J Drug Target ; 15(7-8): 487-95, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17671895

RESUMO

Tetrahydropyranyladriamycin (THP or pirarubicin) destroys tumors via several mechanisms; one of which involves the production of ROS that requires molecular oxygen for its generation. SMA forms stable self-assembled associated micelles with pirarubicin (SMA-pirarubicin), and confers macromolecular characteristics to pirarubicin. This micellar macromolecular drug is selectively delivered to solid tumors via the EPR effect and its preferential tumor accumulation suppresses the systemic toxicity whilst its prolonged high concentration at the site of tumor enhances its efficacy much higher compared to free pirarubicin. Administration of SMA-pirarubicin micelle under HBO can further enhance the delivery of molecular oxygen that facilitates tumor selective generation of ROS, thus augmenting its antitumor potency. In this study, we evaluated the efficacy of SMA-pirarubicin micelles either as single drug or in combination with HBO in a mouse metastatic colorectal cancer model. At or below the maximum tolerated dose, SMA-pirarubicin remarkably reduced metastatic tumor nodules and it was far more effective than free pirarubicin. The data also suggests a potential benefit of combined therapy of HBO with micellar anthracyclins.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/patologia , Doxorrubicina/análogos & derivados , Oxigenoterapia Hiperbárica , Neoplasias Hepáticas/terapia , Animais , Antineoplásicos/efeitos adversos , Terapia Combinada , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Sistemas de Liberação de Medicamentos , Neoplasias Hepáticas/secundário , Masculino , Camundongos , Camundongos Endogâmicos CBA , Micelas , Microscopia Eletrônica de Varredura , Permeabilidade , Espécies Reativas de Oxigênio/metabolismo
15.
HPB (Oxford) ; 9(3): 174-82, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18333218

RESUMO

Liver transplantation is the treatment of choice for end stage liver disease and is often used for primary liver malignancies. The main limitation of its wider application is the availability of suitable donor organs. The use of marginal donor organs, split-liver transplantation and living-related liver transplantation techniques contribute to increase the donor pool. However, the use of these techniques is associated with a higher risk of post transplantation organ dysfunction, predominantly due to ischaemia, preservation and reperfusion injury (IPRI). A number of studies have demonstrated that hyperbaric oxygen (HBO) therapy influences IPRI and consequential acute cellular rejection. This article reviews the rationale of HBO therapy in the field of transplantation with particular emphasis on liver transplantation.

16.
World J Surg ; 30(12): 2112-31, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17102915

RESUMO

One unique feature of tumors is the presence of hypoxic regions, which occur predominantly at the tumor center. Hypoxia has a major impact on various aspects of tumor cell function and proliferation. Hypoxic tumor cells are relatively insensitive to conventional therapy owing to cellular adaptations effected by the hypoxic microenvironment. Recent efforts have aimed to alter the hypoxic state and to reverse these adaptations to improve treatment outcome. One way to increase tumor oxygen tensions is by hyperbaric oxygen (HBO) therapy. HBO therapy can influence the tumor microenvironment at several levels. It can alter tumor hypoxia, a potent stimulus that drives angiogenesis. Hyperoxia as a result of HBO also produces reactive oxygen species, which can damage tumors by inducing excessive oxidative stress. This review outlines the importance of oxygen to tumors and the mechanisms by which tumors survive under hypoxic conditions. It also presents data from both experimental and clinical studies for the effect of HBO on malignancy.


Assuntos
Oxigenoterapia Hiperbárica , Neoplasias/terapia , Apoptose , Hipóxia Celular , Terapia Combinada , Glicólise , Humanos , Neoplasias/metabolismo , Neovascularização Patológica , Espécies Reativas de Oxigênio/metabolismo
17.
Eur J Cancer ; 42(18): 3304-11, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17010602

RESUMO

BACKGROUND AND AIMS: Hyperbaric oxygen (HBO) therapy involves the administration of 100% oxygen at high pressure. It has been used to treat a variety of conditions including non-healing wounds, carbon monoxide poisoning, and as an adjuvant to radiotherapy or chemotherapy. The effect of HBO alone on the growth of malignancy remains controversial. This study investigates the impact of HBO on tumour growth, kinetics and microcirculation of colorectal cancer liver metastases in an experimental model. METHODS: Male CBA mice were induced with colorectal liver metastases via an intrasplenic injection of a murine derived colorectal cell line. Tumours were examined using quantitative stereological analysis, histology and scanning electron microscopy of microvascular resin casts. The effect of HBO on tumour proliferation and apoptosis was quantified using immunohistochemistry. RESULTS: Daily exposure to HBO at 2.4 atm for 90 min had no effect on the volume of liver metastases. At day 13, HBO caused a significant reduction in tumour necrosis and proliferation compared to the non-HBO group (p=0.002 and p=0.008, respectively). By day 25 however, no differences were observed (p>0.05). No differences in apoptosis or microvascular architecture were observed. CONCLUSION: HBO did not have a tumour stimulatory effect on colorectal liver metastases and may potentially be used safely in conjunction with other therapeutic treatment modalities.


Assuntos
Neoplasias Colorretais/patologia , Oxigenoterapia Hiperbárica , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Animais , Divisão Celular , Modelos Animais de Doenças , Imuno-Histoquímica , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos CBA , Microcirculação
18.
J Surg Oncol ; 91(2): 134-40, 2005 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16028287

RESUMO

BACKGROUND AND AIMS: Thalidomide has undergone resurgence in the treatment of specific malignancies. One of the possible actions of thalidomide may be an antiangiogenic effect. This study investigates the effects of thalidomide on tumor growth and long-term survival in a murine model of colorectal liver metastases. METHODS: Liver metastases were produced in male CBA mice by intrasplenic injection of a dimethyl hydrazine induced MoCR colon cancer murine cell line. Thalidomide was administered daily at doses ranging from 50 to 300 mg/kg by intraperitoneal injection. Tumor growth was assessed using quantitative stereological analysis. The effect on long-term survival was determined at the maximum tolerated dose using Kaplan-Meier analysis. The microvascular effects of thalidomide were assessed by laser Doppler flowmetry (LDF) and microvascular resin casting. Immunohistochemistry was used to determine vascular endothelial growth factor (VGEF) and basic fibroblast growth factor (bFGF) expression. RESULTS: Thalidomide, (50-300 mg/kg) caused no significant reduction in tumor growth by day 21 following induction of liver metastases and caused systemic toxicity at a dose of 300 mg/kg. At a dose of 200 mg/kg given beyond 35 days, thalidomide significantly reduced tumor growth compared to control, (P = 0.029). No significant impact on survival was however observed (P = 0.93). LDF and microvascular resin casting showed no differences in blood flow or tumor microvascular architecture. VGEF and FGF were expressed in tumors, but remained unaltered by thalidomide administration compared to matched controls. CONCLUSIONS: Thalidomide caused a significant reduction in the volume of colorectal liver metastases during the late phase of tumor growth. There was however no improvement in survival. Tumor growth reduction in this model did not appear to be due to microvascular changes or altered expression of VGEF or basic FGF. Further investigation into potential mechanisms of action of thalidomide and its synergistic use with other therapies is required.


Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Talidomida/farmacologia , Análise de Variância , Inibidores da Angiogênese/administração & dosagem , Animais , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/metabolismo , Fator 2 de Crescimento de Fibroblastos/biossíntese , Imuno-Histoquímica , Fluxometria por Laser-Doppler , Masculino , Camundongos , Camundongos Endogâmicos CBA , Transplante de Neoplasias , Neovascularização Patológica/patologia , Talidomida/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/biossíntese
19.
J Clin Laser Med Surg ; 20(4): 189-96, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12206720

RESUMO

OBJECTIVE: Our aim in this study was to investigate the characteristics of a diffuser-tipped optical fiber in producing tumor necrosis, compared to a standard bare-tipped fiber. The potential synergistic effect between thermal sensitization by metronidazole and interstitial laser hyperthermia (ILH)-induced tumor necrosis is also evaluated. BACKGROUND DATA: ILH is a minimally invasive technique for the treatment of colorectal liver metastases. One of the major limitations is the size of tissue necrosis achieved by a single optical fiber. Use of cylindrical diffuser-tipped fibers and thermal sensitization of tumor cells by metronidazole may increase the size of tumor necrosis achieved by a single optical fiber. MATERIALS AND METHODS: A model of colorectal cancer liver metastases in male inbred CBA mice was used. Laser hyperthermia was applied to tumor tissue using either a bare optical quartz fiber or a cylindrical diffuser-tipped fiber from a Medilas fibertom 4100 Nd:YAG surgical laser generator. Six hundred joules of energy was applied at two power settings, 5 and 10 watts, using bare- and diffuser-tipped fibers, respectively. The extent of necrosis was assessed by histological techniques. A similar study with three experimental groups was treated with 300 J of applied energy. Extent of immediate tumor necrosis was compared to that seen 24 h after ILH treatment. The third group, which had been treated with intraperitoneal metronidazole prior to ILH, was also assessed for tumor necrosis after 24 h and results compared with both the previous groups. RESULTS: ILH delivered using a cylindrical diffuser-tipped fiber resulted in a significantly larger diameter of tumor necrosis when compared to a bare-tipped fiber, for a given amount of applied energy. The differences were more significant at higher power settings. Six hundred joules of energy applied by ILH using a bare-tipped fiber at 5 and 10 watts produced 6.7 +/- 1.1 mm and 5.9 +/- 0.6 mm diameter of tumor necrosis, respectively. At equivalent settings, the diffuser-tipped fiber produced 7.7 +/- 1.0 mm and 8.1 +/- 0.6 mm diameter of tumor necrosis (p = 0.02 and p < 0.001). Using a diffuser-tipped fiber and an applied energy of 300 J delivered at 5 watts power, mean diameter of tumor necrosis immediately after treatment was 6.7 +/- 1.1 mm and after 24 h 7.9 +/- 1.3 mm (p = 0.006). Mean diameter of tumor necrosis 24 h after ILH in animals treated with metronidazole was 8.3 +/- 1.9 mm (p = 0.11). CONCLUSION: Diffuser-tipped optical fiber appears to significantly increase the diameter of ILH-induced tumor necrosis compared to the bare fiber. In contrast to the bare fiber, it enables the application of laser energy using higher power settings without compromising the diameter of tumor necrosis achieved. In animals treated with metronidazole, a trend towards increased tumor destruction at the tumor-host interface was seen on histolopathology. In addition, a trend towards increased diameter of tumor necrosis was also seen; however, statistical significance was not achieved.


Assuntos
Neoplasias Colorretais/patologia , Hipertermia Induzida/métodos , Terapia a Laser , Neoplasias Hepáticas Experimentais/secundário , Neoplasias Hepáticas Experimentais/terapia , Animais , Masculino , Metronidazol/farmacologia , Camundongos , Camundongos Endogâmicos CBA , Necrose
20.
ANZ J Surg ; 72(6): 450-2, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12121169

RESUMO

The recommended treatment for a focal mass in the head of the pancreas is pancreaticoduodenectomy. Preoperative biopsy is not advised in patients who are candidates for resection because of the documented risk of tumour dissemination along the needle tract and significant false negative results.1 Autoimmune pancreatitis is a relatively uncommon condition that can present as a pancreatic mass and mimic malignancy. It may respond to glucocorticoid therapy, and further assessment of such treatment is indicated.2 Such experience will only accumulate if wider knowledge of this condition leads to clinical suspicion.


Assuntos
Doenças Autoimunes/diagnóstico , Pancreatite/diagnóstico , Adulto , Humanos , Masculino
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