1,720,958 research outputs found
Optimized procedure of real-time systemic leakage monitoring during isolated limb perfusion using a hand held gamma probe and 99mTc-HSA.
No full textIsolated limb perfusion (ILP) therapy using a combination of tumour necrosis factor alpha (TNF) and cytostatic agents in hyperthermic conditions has proven to be effective in treating cancers limited to limbs or to a single organ such as the liver. A critical step for ILP is the accurate and real-time monitoring of systemic leakage with the aim of avoiding severe systemic TNF mediated toxicity. It has been established that TNF toxic effects become relevant when overcoming the 10% limit of the 'effective' therapeutic dose administered during ILP. The most diffuse procedure for systemic leakage monitoring is based on the utilization of human soluble serum albumin (HSA) labelled with I-131 and an external scintillation detector. In order to overcome some drawbacks connected with the properties of I-131, we developed a new procedure based on the utilization of HSA labelled with Tc-99m in combination with a hand held gamma probe used as a detector. Our procedure consists of the following steps: (1) a Tc-99m-HSA dose standardized as 0.5 MBq(.)kg(-1) body weight is injected into the ILP circuit before TNF administration; (2) a hand held gamma probe is placed over the pre-cordial area in a zone pre-marked on the patient's skin during a simulation test; (3) 48-72 h before ILP, a simulation test is obtained using a Tc-99m-HSA dose corresponding to 10% of the dose calculated for ILP (i.e., 0.05 MBq(.)kg(-1) body weight); (4) during the simulation test the maximum count-rate zone detected on the pre-cordial area is marked on patient's skin; (5) a 60 min time-activity curve corresponding to the circulating Tc-99m-HSA radioactivity effective decay is calculated and fitted; and (6) this time-activity curve is used to compensate for the leakage systemic counting observed during ILP. In order to compare the external, probe counting with the circulating radioactivity, in the first 10 patients from a total series of 43 treated patients, the results of external, probe monitoring were compared with the results of patient blood and perfusion circuit samples taken simultaneously every 5 min and measured by a laboratory gamma counter placed in the operating theatre. A good correlation was found between the two methods (R-2 = 0.965, P < 0.01). It is concluded that the proposed procedure, based on the combination of Tc-99m-HSA as the radiotracer and a hand held gamma probe as the detector, appears to be technically simple and accurate enough in the real-time monitoring of perfusion leakage in ILP cancer therapy. Moreover, using Tc-99m-HSA as the radiotracer, the risk of radioactive contamination is significantly lower in comparison with I-131-HSA
Doxorubicin activity is enhanced by hyperthermia in a model of ex vivo vascular perfusion of human colon carcinoma
No full textThere is little information on the pharmacokinetics and pharmacodynamics of doxorubicin (DXR) administered during locoregional treatments of colon carcinoma under hyperthermic conditions. The aim of this study was to evaluate distribution and activity of DXR in healthy tissue and tumor tissues under hyperthermic conditions by using an experimental model of ex vivo isolated vascular perfusion of human colon segments bearing primary carcinoma. The influence of topoisomerase-IIalpha (TPI2alpha) expression on the anti-cancer activity of DXR combined with heat was evaluated as well. Twenty seven colon segments surgically resected for primary carcinoma were perfused ex vivo under physiological conditions (group A, n = 7), with DXR (group B, n = 6), under hyperthermic conditions (group C, n = 6), and with the combination DXR-hyperthermia (group D, n = 8). Samples of perfusate and tissues (normal and pathologic) were collected during 90 minutes of perfusion. Doxorubicin concentration in perfusate and tissues was assessed with high-performance liquid chromatography. Protein expression of TPI2alpha, the main molecular target of DXR, was measured by image analysis in normal mucosa and tumor samples. Drug uptake was increased by heat equally in healthy and diseased tissue. Under hyperthermic conditions, DXR activity was significantly higher in pathologic mucosa than in normal mucosa. Furthermore, the activity of DXR combined with heat correlated with baseline TPI2alpha levels in tumor tissue. From these findings, it appears that heat sensitizes tumor cells-but not normal mucosa-to DXR activity. Furthermore, protein levels of TPI2alpha in pretreatment samples could predict tumor sensitivity to DXR
Induction of endothelial nitric oxide synthase expression by melanoma sensitizes endothelial cells to tumor necrosis factor- driven cytotoxicity
Full text linkPurpose: The cascade of molecular events leading to tumor necrosis factor (TNF)-mediated tumor regression is still incompletely elucidated. We investigated the role of endothelial nitric oxide synthase in determining the tumor-selective activity of TNF.
Experimental Design: Using quantitative real-time PCR, endothelial nitric oxide synthase gene levels were measured in melanoma metastases of the skin and normal skin biopsies obtained from 12 patients before undergoing TNF-based therapy. In vitro, the ability of melanoma cells supernatant to affect endothelial nitric oxide synthase transcription by endothelial cells and the influence of nitric oxide synthase inhibition on TNF cytotoxicity toward endothelial cells was evaluated.
Results: Endothelial nitric oxide synthase transcript abundance resulted significantly greater in tumor samples rather than in normal skin samples and in patients showing complete response to TNF-based treatment rather than in those showing partial/minimal response. In vitro, melanoma cells' supernatant induced endothelial nitric oxide synthase gene expression by endothelial cells. Nitric oxide synthase inhibition slowed endothelial cells proliferation and, if induced before TNF administration, decreased the cytokine-mediated cytotoxicity on endothelial cells.
Conclusions: Taken together, these findings support the hypothesis that high expression of endothelial nitric oxide synthase in the tumor microenvironment might increase or be a marker for endothelial cells sensitivity to TNF. These observations may have important prognostic and/or therapeutic implications in the clinical setting
Hypoxic antiblastic stop-flow limb perfusion: clinical outcome and pharmacokinetic findings of a novel treatment for in transit melanoma metastases.
No full textHypoxic antiblastic stop-flow perfusion (SFP) has recently been proposed as a therapeutic option for patients with locally advanced tumors. We report on the clinical and pharmacological results of our prospective study of limb SFP for the treatment of in transit melanoma metastases. Twenty-three patients with limb-sited melanoma metastases were treated with melphalan (10 mg/l) based pelvic (n=11, group A) or femoral (n=12, group B) SFP under hypoxic conditions. Systemic and locoregional toxicity, tumor response rate, and local progression-free survival were analyzed. Melphalan concentrations were measured in the perfusate and systemic circulation during SFP, and after 30-min hemofiltration. Perfusate-to-plasma leakage was assessed using a scintigraphic method. No postoperative deaths occurred. Mild locoregional toxicity was observed in 5 patients (18%), and systemic toxicity was mild to severe in 8 patients (30%), the incidence being higher in group A. Tumor response rate (complete + partial response) and time to local disease progression were significantly different in group A and B (9% vs 58% and 7 vs 13 months, respectively). The pharmacokinetic study showed that pelvic SFP was associated with a higher leakage rate and a lower area under the curve ratio than femoral SFP (44% vs 31% and 5.6 vs 9.8, respectively). Limb SFP is a feasible and relatively simple procedure. Toxicity and tumor response rates strictly depend upon drug leakage control. Further efforts should be made to exploit the potential anti-tumor activity of this novel locoregional drug delivery system
Molecular detection of circulating tumor cells is an independent prognostic factor in patients with high-risk cutaneous melanoma
No full textDetection of circulating tumor cells (CTCs) might improve current staging procedures by identifying a subgroup of patients with minimal residual disease and thus a higher risk of disease recurrence. Forty patients with greater than or equal to2-mm-thick cutaneous melanoma with or without lymph node metastasis were enrolled. After standard radical surgery and adjuvant therapy in case of lymph node metastasis, patients were followed up with routine physical and radiologic assessments as well as serial PCR-based analysis of CTCs using 2 melanoma markers (tyrosinase and Melan-A/Mart-I). After a median follow-up of 30 months, 18 patients had disease recurrence and 28 were PCR-positive before the disease became clinically evident. The sensitivity of the molecular test was 83%. Median time to PCR positivity and median PCR-to-relapse time were 12 and 8 months, respectively. At multivariate analysis, PCR positivity was an independent predictor of disease recurrence (hazard ratio = 2.06, 95% Cl 1.07-3.35; p = 0.03). Among high-risk melanoma patients, serial PCR-based analysis of CTCs can identify a subgroup at higher risk of disease recurrence, with clinically significant advance. Therefore, CTC detection might be employed for the selection of patients for adjuvant treatment and during follow-up for early indication of therapeutic failure
True versus mild hyperthermia during isolated hepatic perfusion: effects on melphalan pharmacokinetics and liver function
No full textHyperthermic antiblastic isolated hepatic perfusion (IHP) with
melphalan has been recently proposed as an alternative therapeutic option for patients with unresectable liver tumors. Although melphalan–heat antiblastic synergism is at a maximum at temperatures higher than 41°C, IHP
has so far been performed in humans at lower temperatures. In this experimental work, we compared IHP under mild versus true hyperthermic conditions in terms of drug pharmacokinetics and liver function. Ten pigs were
submitted to IHP with melphalan 1.5 mg/kg at a mean temperature of 40°C (group A, n = 5) or 42°C (group B, n = 5). After a 60-minute perfusion, a 15-minute washout was performed. Perfusate-to-plasma leakage was monitored using scintigraphy. Throughout perfusion, samples from the sys-
temic blood, perfusate, and liver parenchyma were obtained to measure melphalan concentrations. Liver function was assessed using standard blood tests and the indocyanine green-based test. No deaths related to the IHP procedure were recorded. All animals had transient liver function im-
pairment, with all liver function test results returning to normal within the observation period. At histologic examination, liver damage was similar under both hyperthermic conditions. Melphalan levels in the perfusate
were not significantly different in the two study groups (the mean perfusate/plasma area under the curve from 0 to 60 minutes ratios were 463 and 501, respectively). These results correlated well with those obtained using the scintigraphic method. Liver drug concentrations remained unchanged
after true hyperthermia IHP. Under true hyperthermic conditions, neither an increase in liver parenchyma toxicity nor changes in melphalan pharmacokinetics were observed. These findings support the use of true hyperthermia in the clinical setting to exploit fully the antitumor synergism be-
tween melphalan and heat
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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