Management of the extravasation of anti-neoplastic agents.

BACKGROUND: Extravasation is a potentially severe complication that can occur during the administration of chemotherapy. The scarcity of evidence available makes it difficult to develop an optimal management scheme. The purpose of this guideline is to review the relevant scientific literature on the prevention, management, and treatment of extravasation occurring during the administration of chemotherapy to cancer patients. METHOD: A scientific literature review was conducted using the PubMed search tool. The period covered was from database inception to April 2014, inclusively. Since the literature on extravasation treatment is often empirical, anecdotal, and controversial, the review also identified clinical practice guidelines and expert consensuses published by relevant international organizations and cancer agencies. RESULTS: Identification of potential risk factors and preventive measures can reduce the risk of extravasation. Recognition and management of symptoms are crucial in patients with this complication. Provision of adequate instruction to personnel responsible for administering chemotherapy and to patients on recognizing symptoms, preventing, and managing extravasation is essential. Extravasation can be treated with dry warm or cold compresses and various antidotes such as dimethyl sulfoxide, dexrazoxane, hyaluronidase, or sodium thiosulfate, depending on the agent that has caused extravasation. Patient monitoring to assess the progression or regression of symptoms and to thus take the appropriate measures is necessary. CONCLUSION: Several strategies must be established to ensure that extravasation is recognized and properly managed. Given the evidence available at this time, the Comité de l'évolution des pratiques en oncologie (CEPO) has made recommendations for clinical practice in Quebec.

Decay pattern of pygmy states observed in neutron-rich 26Ne.

Coulomb excitation of the exotic neutron-rich nucleus (26)Ne on a (208)Pb target was measured at 58 MeV/u in order to search for low-lying E1 strength above the neutron emission threshold. This radioactive beam experiment was carried out at the RIKEN Accelerator Research Facility. Using the invariant mass method in the 25Ne+n channel, we observe a sizable amount of E1 strength between 6 and 10 MeV excitation energy. By performing a multipole decomposition of the differential cross section, a reduced dipole transition probability of B(E1)=0.49+/-0.16e(2) fm(2) is deduced, corresponding to 4.9+/-1.6% of the Thomas-Reiche-Kuhn sum rule. For the first time, the decay pattern of low-lying strength in a neutron-rich nucleus is measured. The extracted decay pattern is not consistent with several mean-field theory descriptions of the pygmy states.

Reduction of the spin-orbit splittings at the n = 28 shell closure.

The N = 28 shell closure has been investigated via the 46Ar(d,p)47Ar transfer reaction in inverse kinematics. Energies and spectroscopic factors of the neutron p(3/2), p(1/2), and f(5/2) states in 47Ar were determined and compared to those of the 49Ca isotone. We deduced a reduction of the N = 28 gap by 330(90) keV and spin-orbit weakenings of approximately 10(2) and 45(10)% for the f and p states, respectively. Such large variations for the f and p spin-orbit splittings could be accounted for by the proton-neutron tensor force and by the density dependence of the spin-orbit interaction, respectively. This contrasts with the picture of the spin-orbit interaction as a surface term only.

Inhaled prostacyclin reduces cardiopulmonary bypass-induced pulmonary endothelial dysfunction via increased cyclic adenosine monophosphate levels.

OBJECTIVE: Cardiopulmonary bypass triggers a systemic inflammatory response that alters pulmonary endothelial function, which can contribute to pulmonary hypertension. This study was designed to demonstrate that inhaled prostacyclin, a selective pulmonary vasodilator prostaglandin, prevents pulmonary arterial endothelial dysfunction induced by cardiopulmonary bypass. METHODS: Three groups of Landrace swine were compared: control without cardiopulmonary bypass (control group); 90 minutes of normothermic cardiopulmonary bypass (bypass group); 90 minutes of cardiopulmonary bypass and treated with prostacyclin during cardiopulmonary bypass (continuous nebulization with continuous positive airway pressure until the end of the cardiopulmonary bypass; prostacyclin group). After 60 minutes of reperfusion, swine were put to death and pulmonary arteries harvested. After contraction to phenylephrine, endothelium-dependent relaxation to bradykinin and acetylcholine was studied in standard organ chamber experiments. The pulmonary artery intravascular cyclic adenosine monophosphate content was compared between the 3 groups (post-cardiopulmonary bypass). RESULTS: There was a statistically significant improvement of the endothelium-dependent relaxation to bradykinin in the prostacyclin group when compared with the bypass group (P <.05). There was no statistically significant difference for endothelium-dependent relaxation to acetylcholine (P >.05) between the prostacyclin and the bypass groups. There was a statistically significant decrease in the cyclic adenosine monophosphate content and a statistically significant increase of the mean pulmonary artery pressure in the bypass group only (P <.05). CONCLUSION: Prophylactic use of inhaled prostacyclin has a favorable impact on the pulmonary endothelial dysfunction induced by cardiopulmonary bypass associated with preservation of pulmonary intravascular cyclic adenosine monophosphate content and the pulmonary vascular tone.

[Extracorporeal circulation: an extraordinary tool that is not just for cardiac surgeons]. / La circulation extra-corporelle: un extraordinaire outil qui n'est pas seulement au service du chirurgien cardiaque.

Extracorporeal circulation (ECC) is not only used for open heart surgery. There are also other surgical and medical applications. ECC can be used for encephalic arteries surgery to induce hypothermia and maximally protect the brain. Femoro-femoral ECC may be needful for urgent traumatologic surgery of the supra-aortic trunci. Intracranial aneurysm repair can occasionally necessitate deep hypothermia and circulatory arrest with ECC. Renal cell carcinomas may metastasize to the right atrium and surgery with ECC is mandatory for complete excision. Some reports in the literature mention use of ECC for hepatic surgery of intra-hepatic aneurysms. With acute peripheral ischemia, metabolites in the affected limb can be washed out with good results. Medical indications for ECC are numerous with pulmonary assistance as one of the foremost when mechanical ventilation failed. Homogeneous and rapid rewarming of hypothermic patients can be achieved with ECC. Finally, some groups have reported the use of ECC to administer chemotherapy in limb melanoma.

[Chronic constrictive pericarditis in African children: report of a case]. / Péricardite chronique constrictive chez l'enfant africain: à propos d'un cas.

The chronic constrictive pericarditis is a rare affection, with multiple etiologies and concerning especially the adult. We report a case of chronic constrictive pericarditis in an African child in whom no etiology was found. A review of the literature raises the characteristics of chronic constrictive pericarditis for a better therapeutic management.

Characterization of Cdk2-cyclin E complexes in plasma membrane and endosomes of liver parenchyma. Insulin-dependent regulation.

Rat liver parenchyma Golgi/endosomes fractions harbor a tyrosine-phosphorylated 34-kDa protein. Screening of Golgi, endosomes (ENs), plasmalemma (PM), and cytosolic (Cyt) fractions revealed the presence of the mitotic kinase Cdk2 in ENs, PM, and Cyt. The fluid phase endocytic marker horseradish peroxidase gained access to the endosomal Cdk2, confirming its localization. Cdk2 was shown to be associated to cyclin E and was active in ENs and PM fractions. The administration of a single dose of insulin (1.5 microgram/100 g, body weight) induced a time-dependent activation of the insulin receptor kinase in these structures. Insulin receptor-kinase activation was followed by the inhibition of immunoprecipitated Cdk2-cyclin E kinase activity in PM and the progressive disappearance of cyclin E. In marked contrast, no such effect was observed in ENs. The injection of a phosphotyrosyl phosphatase inhibitor (bpV(phen)) increased the levels of cyclin E in ENs and PM. A massive recruitment of p27(kip1) was observed in the Cdk2-cyclin E complexes isolated from PM and Cyt but not from ENs. In vitro, Cdk2-cyclin E complexes have the capacity to inhibit the formation of hybrid structures containing horseradish peroxidase and radioiodinated epidermal growth factor. Therefore, in the PM and ENs of adult rat liver, an active and regulated pool of the mitotic kinase Cdk2-cyclin E and some yet to be defined effectors are present. Cdk2 may contribute to the modulation of transport events and/or maintenance of the topology of endocytic elements.

Compartmentalization of the mitogen-activated protein kinase (MAPK) in hepatic endosomes: association with the internalized epidermal growth factor (EGF) receptor.

A pool of MAPK was found in hepatic plasma membrane (PM) and endosomes (ENs). After injection of a single dose of EGF (10 microg/100 g body weight), MAPK was detected in EGF receptor (EGFR) immunoprecipitates prepared from ENs. MAPK was detected in a time-dependent manner in EGFR immunoprecipitates that was coincident with the progressive concentration of the EGFR. The EGFR-associated MAPK was also detected by using an anti-phospho-MAPK suggesting that it was active. MAPK was present in wheat-germ agglutinin (WGA) eluates prepared from ENs and was maximally tyrosine-phosphorylated at the time peak of EGFR internalization. MAPK therefore is compartmentalized in PM and ENs of rat liver. A fraction of the endosomal MAPK was found to be associated with the internalized EGFR complexes, suggesting that it plays a role in the control of the EGFR activity at this locus.

Protein model determination from crystallographic data.

Crystallographic studies play a major role in current efforts towards protein structure determination. However, despite recent advances in computational tools for molecular modeling and graphics, the task of constructing a model of the tertiary structure of a protein from experimental data remains complex and time-consuming, requiring extensive expert intervention. This paper describes an approach to protein model determination that incorporates crystallographic data, along with sequence data. A model is represented as an annotated graph that traces the backbone and side chains for a protein. The proposed approach incorporates numerical techniques that are applied to construct and analyze an electron density map for a unit cell of a crystal. The purpose of this work is to advance the ability to discern meaningful features of protein structure through the use of topological analysis of the relative density. Experimental results, which demonstrate the viability of the approach, are reported.

Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUC1 mucin. San Diego, Calif., November 17-23, 1996.

Sixteen research groups participated in the ISOBM TD-4 Workshop in which the reactivity and specificity of 56 monoclonal antibodies against the MUC1 mucin was investigated using a diverse panel of target antigens and MUC1 mucin-related synthetic peptides and glycopeptides. The majority of antibodies (34/56) defined epitopes located within the 20-amino acid tandem repeat sequence of the MUC1 mucin protein core. Of the remaining 22 antibodies, there was evidence for the involvement of carbohydrate residues in the epitopes for 16 antibodies. There was no obvious relationship between the type of immunogen and the specificity of each antibody. Synthetic peptides and glycopeptides were analyzed for their reactivity with each antibody either by assay of direct binding (e.g. by ELISA or BiaCore) or by determining the capacity of synthetic ligands to inhibit antibody binding interactions. There was good concordance between the research groups in identifying antibodies reactive with peptide epitopes within the MUC1 protein core. Epitope mapping tests were performed using the Pepscan analysis for antibody reactivity against overlapping synthetic peptides, and results were largely consistent between research groups. The dominant feature of epitopes within the MUC1 protein core was the presence, in full or part, of the hydrophilic sequence of PDTRAPAP. Carbohydrate epitopes were less easily characterized and the most useful reagents in this respect were defined oligosaccharides, rather than purified mucin preparations enriched in particular carbohydrate moieties. It was evident that carbohydrate residues were involved in many epitopes, by regulating epitope accessibility or masking determinants, or by stabilizing preferred conformations of peptide epitopes within the MUC1 protein core. Overall, the studies, highlight concordance between groups rather than exposing inconsistencies which gives added confidence to the results of analyses of the specificity of antimucin monoclonal antibodies.

Analysis of the role of type 1 core O-glycans in the binding of anti-MUC1 antibodies by cytofluorometry and synthetic peptide/glycopeptide binding inhibition studies.

A panel of 56 MAbs submitted to the ISOBM TD-4 (MUC1) Workshop were analysed in two systems. These systems were designed to screen for peptide type 1 core O-glycan-related reactivities. Using synthetic MUC1 mucin-related peptides and glycopeptides, the panel of MAbs were tested for relative binding affinities to type 1 core O-glycan-substituted MUC1 structures. These studies utilized a competitive binding format with a native human adenocarcinoma-derived mucin as a solid phase. This system allows for analysis of the type 1 core glycoform subspecificity of each MAb. The second approach taken in parallel, utilized MCF-7 (BrCa) and OVCAR (OVCa) cell lines which were grown in the presence or absence of phenyl-N-acetylgalactosaminide (p-gal), a blocker of mucin O-linked glycosylation. These cells were analysed by FACS to examine the role these same glycan substitutions play with regard to either the diagnostic or therapeutic application of these MAbs. By FACS analysis there was a consistent increased 'epitope exposure' for peptide-specific MAbs binding in the presence of p-gal. In addition, a single MAb (TD-4 #150) is interpreted to react with a type 1 core O-glycan, probably with Tn, TF or STn specificity.

Protein model representation and construction.

Crystallographic studies play a major role in current efforts towards protein structure determination. However, despite recent advances in computational tools for molecular modeling and graphics, the task of constructing a protein model from crystallographic data remains complex and time-consuming, requiring extensive expert intervention. This paper describes an approach to automating the process of model construction, where a model is represented as an annotated trace (or partial trace) of the three-dimensional backbone of the structure. Potential models are generated using an evolutionary algorithm, which incorporates multiple fitness functions tailored to different structural levels in the protein. Preliminary experimental results, which demonstrate the viability of the approach, are reported.

Effect of thyroid hormones on G proteins in synaptosomes of chick embryo.

We have described a thyroid hormone receptor in synaptosomes of the chick embryo brain. To understand how the hormones exert their actions at this level, we performed a series of studies to demonstrate that this receptor could be linked to G proteins. Guanosine 5'-[gamma-thio]triphosphate (GTP gamma S)(100 muM) lowered the binding capacity of the receptor high affinity site from 8.9 +/- 1.3 to 3.4 +/- 1.3 ng T3/mg protein, a finding consistent with the coupling of receptor to G proteins. Furthermore, ADP ribosylation with pertussis toxin showed that thyroid hormones induced a dose-dependent increase in the inactive alpha 0-subunit of the G0 protein. This effect was detected at 10 pM, with a maximal increase (mean +/- SEM, 50 +/- 3.6%) at 100 nM, and T4 was as effective as T3. Both hormones also decreased the intrinsic guanine triphosphatase activity of G proteins by lowering the binding of GTP to the alpha-subunit and their rate of hydrolysis. This inhibition was greater with T4 (25 +/- 5%) than with T3 (14 +/- 2%), suggesting that the former could be the more active hormone at the synaptosomal level. The effect on guanine triphosphatase activity confirms that the synaptosomal thyroid hormone receptor is coupled to a G(zero) protein. These results demonstrate that thyroid hormones increase or favor the ADP ribosylation of G alpha(zero) by pertussis toxin. Thus, they enhance the alpha(zero)-GDP form of the G(zero) protein, namely its inactive conformation. By decreasing the activity of this protein, these hormones may modulate the formation of second messengers in synaptosomes and intervene in the regulation of neuronal proliferation and differentiation induced by several factors. Therefore, thyroid hormones may exert their action on brain maturation at least in part by modulating G alpha(zero) through their synaptosomal receptor.