ABSTRACT
BACKGROUND: The CXCL12-CXCR4 chemokine axis plays an important role in cell trafficking as well as in tumor progression. In colorectal cancer (CRC), the chemokine receptor CXCR4 has been shown to be an unfavorable prognostic factor in some studies, however, the role of its activated (phosphorylated) form, pCXCR4, has not yet been evaluated. Here, we aimed to investigate the prognostic value of CXCR4 and pCXCR4 in a large cohort of CRC patients. PATIENTS AND METHODS: A tissue microarray (TMA) of 684 patient specimens of primary CRCs was analyzed by immunohistochemistry (IHC) for the expression of CXCR4 and pCXCR4 by tumor cells and tumor-infiltrating immune cells (TICs). RESULTS: The combined high expression of CXCR4 and pCXCR4 showed a favorable 5-year overall survival rate (68%; 95%CI = 59-76%) compared to tumors showing a high expression of CXCR4 only (48%; 95%CI = 41-54%). High expression of pCXCR4 was significantly associated with a favorable prognosis in a test and validation group (p = 0.015 and p = 0.0001). Moreover, we found that CRCs with a high density of pCXCR4+ tumor-infiltrating immune cells (TICs) also showed a favorable prognosis in a test and validation group (p = 0.054 and p = 0.004). Univariate Cox regression analysis for TICs revealed that a high density of pCXCR4+ TICs was a favorable prognostic marker for overall survival (HR = 0.97,95%CI = 0.96-1.00; p = 0.01). In multivariate Cox regression survival analyses a high expression of pCXCR4 in tumor cells lost its association with a better overall survival (HR = 0.99; 95%CI = 0.99-1.00, p = 0.098). CONCLUSION: Our results show that high densities of CXCR4 and pCXCR4 positive TICs are favorable prognostic factors in CRC.
Subject(s)
Colorectal Neoplasms/metabolism , Receptors, CXCR4/metabolism , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Confidence Intervals , Humans , Immunohistochemistry , Phosphorylation/genetics , Phosphorylation/physiology , Proportional Hazards Models , Receptors, CXCR4/genetics , Retrospective Studies , Signal Transduction/genetics , Signal Transduction/physiology , Software , Survival Rate , Tissue Array AnalysisABSTRACT
BACKGROUND: The immune contexture predicts prognosis in human colorectal cancer (CRC). Whereas tumour-infiltrating CD8+ T cells and myeloid CD16+ myeloperoxidase (MPO)+ cells are associated with favourable clinical outcome, interleukin (IL)-17-producing cells have been reported to correlate with severe prognosis. However, their phenotypes and functions continue to be debated. OBJECTIVE: To investigate clinical relevance, phenotypes and functional features of CRC-infiltrating, IL-17-producing cells. METHODS: IL-17 staining was performed by immunohistochemistry on a tissue microarray including 1148 CRCs. Phenotypes of IL-17-producing cells were evaluated by flow cytometry on cell suspensions obtained by enzymatic digestion of clinical specimens. Functions of CRC-isolated, IL-17-producing cells were assessed by in vitro and in vivo experiments. RESULTS: IL-17+ infiltrates were not themselves predictive of an unfavourable clinical outcome, but correlated with infiltration by CD8+ T cells and CD16+ MPO+ neutrophils. Ex vivo analysis showed that tumour-infiltrating IL-17+ cells mostly consist of CD4+ T helper 17 (Th17) cells with multifaceted properties. Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release. Consistent with these findings, the presence of intraepithelial, but not of stromal Th17 cells, positively correlated with improved survival. CONCLUSIONS: Our study shows the dual role played by tumour-infiltrating Th17 in CRC, thus advising caution when developing new IL-17/Th17 targeted treatments.
Subject(s)
Colorectal Neoplasms/immunology , Interleukin-17/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Th17 Cells/immunology , Th17 Cells/metabolism , Adult , Aged , Aged, 80 and over , CD8-Positive T-Lymphocytes/immunology , Chemokine CCL20/metabolism , Chemokine CCL5/genetics , Chemokine CCL5/metabolism , Chemokine CXCL10/genetics , Chemokine CXCL9/genetics , Colorectal Neoplasms/pathology , Female , HT29 Cells , Humans , Interleukin-17/analysis , Interleukin-17/genetics , Interleukin-8/metabolism , Lymphocytes, Tumor-Infiltrating/chemistry , Male , Middle Aged , Neutrophils/chemistry , Neutrophils/enzymology , Neutrophils/immunology , Peroxidase/analysis , Phenotype , Prognosis , Receptors, IgG/analysis , Survival Rate , T-Lymphocytes, Cytotoxic/immunology , Th17 Cells/chemistryABSTRACT
BACKGROUND AND OBJECTIVE: Subarachnoid block is a widely used technique for Caesarean section. Its quality can be improved by adding opioids to the local anaesthetics. We studied the quality of the block and its maternal-fetal repercussions when different doses of sufentanil were combined with hyperbaric bupivacaine using the intrathecal route in pregnant women undergoing Caesarean section. METHODS: This was a prospective, randomized, double-blind, controlled trial with 80 pregnant women, ASA I-II, who were scheduled for elective Caesarean section under subarachnoid block. Patients were distributed into four groups according to the dose of sufentanil used: no sufentanil (Group 1, control) or 2.5, or 5.0 or 7.5 microg sufentanil (Groups 2-4, respectively). In every group, the local anaesthetic used was hyperbaric bupivacaine 0.5% (12.5 mg) and the total volume of the solution 4 mL. The onset time of the block, maximum level of sensory block, motor block level, duration of analgesia, maternal side-effects and maternal-fetal cardiovascular repercussions were evaluated. RESULTS: Onset of the block was significantly shorter in the groups receiving opioids compared with the control group. Analgesia was significantly prolonged in Groups 3 and 4. The occurrence of pruritus and somnolence was significantly higher in the group receiving sufentanil 7.5 microg than in other groups. With the exception of pruritus, no differences were observed between groups with respect to cardiovascular or other maternal effects. CONCLUSIONS: The addition of sufentanil 5.0 and 7.5 microg to hyperbaric bupivacaine provided adequate anaesthesia for Caesarean section and good postoperative analgesia. Pruritus was the most common side-effect and had a significantly higher incidence when a dose of sufentanil 7.5 microg was used.
Subject(s)
Anesthesia, Obstetrical , Bupivacaine/therapeutic use , Cesarean Section , Nerve Block/methods , Sufentanil/therapeutic use , Adult , Analysis of Variance , Anesthesia, Obstetrical/methods , Anesthesia, Spinal , Anesthetics, Combined/therapeutic use , Anesthetics, Intravenous/adverse effects , Anesthetics, Intravenous/therapeutic use , Anesthetics, Local/therapeutic use , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Pregnancy , Pregnancy Outcome , Prospective Studies , Subarachnoid Space/physiology , Sufentanil/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND AND OBJECTIVE: Situations may occur in anaesthetic practice where the use of neuromuscular blocking drugs is unsuitable or contraindicated. We investigated the use of propofol given 5 min after fentanyl to permit endotracheal intubation in children. METHODS: We studied the intubating conditions and cardiovascular parameters in 60 ASA I and II children. Intravenous midazolam (0.1 mg kg(-1)) was given as premedication 5 min before the induction of anaesthesia. The children received different doses of propofol (group I, 2.5 mg kg(-1); group II, 3.0 mg kg(-1); group III, 3.5 mg kg-1) preceded by fentanyl (3.0 microg kg(-1)) given 5 min earlier. No neuromuscular blocking agents were administered. The intubating conditions were assessed using a four-point scoring system based on the degree of difficulty of laryngoscopy, the position of vocal cords and the intensity of coughing. RESULTS: Tracheal intubating conditions were adequate in 20% of the patients in group I, in 75% of the patients in group II and in 80% of the patients in group III (P < 0.05 for group I vs. groups II and III). Haemodynamic changes were not significantly different between the groups. CONCLUSIONS: Propofol (3.0 mg kg(-1)) preceded by fentanyl (3.0 microg kg(-1)) was adequate for the induction of anaesthesia in children and provided adequate tracheal intubating conditions without significant haemodynamic changes. This method represents a useful alternative technique for tracheal intubation when neuromuscular blocking drugs are contraindicated or should be avoided.
Subject(s)
Anesthetics, Intravenous , Hypnotics and Sedatives , Intubation, Intratracheal , Propofol , Child , Child, Preschool , Dose-Response Relationship, Drug , Female , Hemodynamics/drug effects , Humans , Hypnotics and Sedatives/administration & dosage , Infant , Male , Propofol/administration & dosage , Vocal Cords/physiologyABSTRACT
Rapid inhalation induction (RII) was successfully employed for patients without myopathy. Inhalatory agents can be used for anaesthetic induction of myasthenics, avoiding the use of neuromuscular blocking agents. We studied the use of RII in 15 myasthenics (MG) and in 15 normal subjects (nMG), measuring induction time (TI), cardiorespiratory effects, complications, and evaluated the patient's reaction to RII. The patients were submitted to elective transsternal thymectomy (MG) and gynaecological or lower abdominal surgery (nMG). No premedication was used. After preoxygenation, RII was started using a mixture of 4% halothane and O2:N2O (1:2). They performed three vital capacity breaths, followed by normal spontaneous ventilation. The TI was assessed by timing the loss of verbal command (TLVC) and loss of eyelid reflex (TLER). Systolic and diastolic pressure, pulse oximetry, capnometry, respiratory rate (RR) and heart rate (HR) were measured during induction at each minute, for four minutes. After a postanaesthetic questionnaire only two normal subjects did not like the RII technique. Mean values for TLVC and TLER were 67 and 73 sec for MG and 64 and 69 sec for nMG, respectively. There was no change in HR for MG or blood pressure. The RR increased in both groups, but no change in PetCO2 was observed; SaO2 was > 97%. In conclusion, RII can be performed rapidly and safely in myasthenic patients and is a technique that should be considered for the induction of anaesthesia in myasthenic patients.
Subject(s)
Anesthesia, Inhalation/methods , Halothane/administration & dosage , Myasthenia Gravis , Nitrous Oxide/administration & dosage , Adult , Blood Pressure/drug effects , Carbon Dioxide/metabolism , Female , Halothane/adverse effects , Halothane/pharmacology , Heart Rate/drug effects , Humans , Incidence , Male , Memory/drug effects , Nitrous Oxide/adverse effects , Nitrous Oxide/pharmacology , Oxygen/blood , Patient Satisfaction , Respiration/drug effects , Time Factors , Vital CapacitySubject(s)
Dogs , Animals , Etomidate/pharmacology , Perfusion , Intracranial Pressure , Infusions, Intravenous , Injections, IntravenousSubject(s)
Pancuronium/administration & dosage , Torticollis/drug therapy , Adult , Female , Humans , Male , Middle Aged , Torticollis/diagnosisABSTRACT
A quetamina foi utilizada para estimulacao de focos epilepticos durante a cirurgia para exerese de area epileptogenica em 3 pacientes com epilepsia temporal (grupo 2) e para o registro de atividade eletrica cerebral em 2 portadores de epilepsia focal (grupo 2). Nos tres pacientes do grupo 1, a droga desencadeou e agravou crises EEG e ECoG tipicas de epilepsia. Nos dois casos de epilepsia focal, houve desaparecimento das crises psico-motoras pre-existentes e individualizacao do foco original fenomenos que regrediram apos 20 e 30 minutos. Em todos os doentes houve aparecimento do tracado EEG tipico do efeito da droga. O periodo pos-operatorio dos casos do grupo 1 caracterizou-se por crises convulsivas generalizados e prolongadas, que cederam com altas doses de anticonvulsivantes. Nos do grupo 2, as crises de epilepsia focal reapareceram, acompanhadas de alucinacoes auditivas e visuais que regrediram em dois dias
Subject(s)
Child, Preschool , Child , Adolescent , Adult , Humans , Anesthesia, Intravenous , Epilepsy , KetamineABSTRACT
Säo analisados vários aspectos das interaçöes da anestesia com anticonvulsivantes, antidepressivos tricíclicos, inibidores da MAO, sais lítio, L DOPA e antineoplásicos. Também säo revistos os principais aspectos clínicos das doenças nas quais essas drogas säo utilizadas, bem como seus efeitos tóxicos e a conduta anestésica nos doentes em uso desses medicamentos
Subject(s)
Humans , Anesthesia , Anticonvulsants , Antidepressive Agents, Tricyclic , Antineoplastic Agents , Drug Interactions , Levodopa , Lithium Chloride , Monoamine Oxidase InhibitorsABSTRACT
A quetamina foi estudada em camundongos e coelhos, quanto a sua acao sobre a sedacao, analgesia, tono muscular, convulsao, agressividade espontanea, ataxia, reflexo de endireitamento, atividade exploradora e outros efeitos. A intensidade desses efeitos foi estudada tambem com a associacao dessa droga com estimulantes do sistema nervoso central (estricnina e pentetrazol) e sedativos (clonazepam e droperidol). Os resultados mostraram que a quetamina produz efeitos excitatorios no camundongo e sedativos nos coelhos, nas doses empregadas. Em camundongos a quetamina antagoniza as convulsoes do pentetrazol e intensifica as da estricnina. Em coelhos inibe os efeitos de ambos os estimulantes.O clonazepam e o droperidol sao capazes de inibir os efeitos excitatorios da quetamina em camundongos
Subject(s)
Animals , Mice , Ketamine , Seizures , Anesthesia, Intravenous , RabbitsABSTRACT
Sao estudados os mecanismos gerais das interacoes medicamentosas, em especial aqueles que sao mais importantes para a anestesia
Subject(s)
Anesthetics , Drug InteractionsABSTRACT
E apresentado um caso de acidente anestesico em paciente viciado em cocaina, devido a interacao dessa droga com halotano e quetamina. Sao discutidos os principais aspectos farmacologicos e clinicos do uso de cocaina, bem como suas implicacoes com a anestesia
Subject(s)
Adult , Humans , Male , Anesthesia , Anesthetics , Cocaine , Substance-Related Disorders , Halothane , KetamineABSTRACT
Foi estudado o efeito da injecao venosa de quetamina (2 mg. Kg1) em caes anestesiados com pentobarbital sodico. Os animais foram distribuidos em tres grupos de seis, de acordo com o tipo de ventilacao. Grupo I ventilacao espontanea; Grupo II - ventilacao artificial com ar; Grupo III - ventilacao artificial com oxigenio a l00%. Os resultados, analisados estatisticamente pelo teste T de Student mostraram que a quetamina nao foi capaz de reverter a hipotensao arterial induzida pelo diazoxido, nos animais dos tres grupos. Pelo contrario, apos 15 minutos de sua administracao, houve queda da pressao arterial, mais acentuada que a induzida pelo diazoxido isoladamente. Sao discutidos os mecanismos envolvidos nesses efeitos, bem como suas implicacoes em clinica
Subject(s)
Animals , Dogs , Anesthesia, Intravenous , Diazoxide , Drug Interactions , KetamineABSTRACT
Foi estudada a interacao do agente citotoxico alquilante oncotiotepa com o brometo de fazadinio e cloreto de succinilcolina, sobre a juncao mioneural de 35 caes adultos. As drogas foram estudadas isoladamente e em associacao, sendo os resultados comparados entre si. Observou-se que a oncotiotepa, isoladamente, nao altera a funcao da juncao mioneural, em administracao aguda; porem e capaz de prolongar o bloqueio mioneural induzido pelo cloreto de succinilcolina mas nao o do brometo de fazadinio
Subject(s)
Animals , Dogs , Drug Interactions , Neuromuscular Nondepolarizing Agents , Pyridinium Compounds , Succinylcholine , ThiotepaABSTRACT
O acido ioxitalamico, um contraste radiologico que induz raramente a efeitos colaterais, foi estudado na dose de 0,1 mg/kg, isoladamente e em associacao com o brometo de pancuronio (0,04 mg/kg) e com o cloreto de succinilcolina (0,5 mg/kg) quanto a sua acao sobre a funcao mioneural de 30 caes.Os resultados mostraram que esse contraste nao atua isoladamente ou associado aos agentes curarizantes, sobre a juncao mioneural, nem altera o efeito destes. Entretanto, um animal apresentou efeito mio-relaxante prolongado, com associacao do contraste com o brometo de pancuronio. Dois caes, descartados da experiencia, apresentaram reacoes anafilaticas com o contrast
Subject(s)
Animals , Dogs , Drug Interactions , Iothalamic Acid , Neuromuscular Depolarizing Agents , Neuromuscular Nondepolarizing AgentsSubject(s)
Humans , Male , Female , Droperidol , Fentanyl , Hypophysectomy , Neuroleptanalgesia , Nitrous Oxide , Postoperative ComplicationsABSTRACT
Sao revistos os aspectos mais importantes, fisiologicos, fisiopatologicos e farmacologicos, relacionados com a anestesia para neurocirurgia. A pressao intracraniana e estudada quanto ao seu conceito e aos fatores que a determinam. Sao enfatizados os problemas relacionados com o fluxo sanguineo e o edema cerebral, principalmente os devidos a anestesia. Os aspectos mais importantes da anestesia para neurocirurgia sao discutidos, como o preparo do doente, a indicacao de drogas e tecnicas, a ventilacao, as modificacoes das funcoes vitais e a monitorizacao. Sao tambem analisadas as tecnicas de anestesia para traumatismos de cranio e craniectomias de fossa posterior
