Fluoropyrimidine chemotherapy in a rat model: comparison of fluorouracil metabolite profiles determined by high-field 19F-NMR spectroscopy of tissues ex vivo with therapy response and toxicity for locoregional vs systemic infusion protocols

A Sprague-Dawley rat model with DS sarcoma transplanted in the thigh was used to compare transcatheter locoregional i.a. and systemic i.v. administration of 5-fluorouracil (FU) at 12 dose-rate schedules: 25, 50 and 100 mg/kg; bolus, 1, 5 and 24 h infusions. In experiment A tumor (62/67 animals) as well as liver and kidney (56/67 animals) were excised 1 h after a single bolus or 1 h infusion or at the end of 5 and 24 h infusions. (19)F-NMR spectroscopy at 11.7 T was used to quantitate FU and its metabolites in ca. 1 g of tissue at 4 degrees C. In experiment B analogous FU treatments were repeated for 5 days (rats 80+11 controls). Tumor volumes vs time, various blood parameters and survival times were recorded, and a log growth rate parameter log GR, a response index RI, and a toxicity index TI were calculated. The i.a. vs i.v. ratios for tumor concentrations of FU and total anabolites (F-Nucl) were >1 for nearly all treatments and increased with infusion time at the higher doses. F-Nucl in tumor correlated linearly with total fluorine concentration (Tot. F range 30-1100 nmol/g) over all treatments (r=0.92, slope=0.45, p<0.0001). For non-bolus i.v. treatments [FU+F-Nucl] decreased linearly with decreasing FU dose rate (r(2)=0.74, zero intercept), while i.a. treatments showed non-linear behavior. For non-bolus treatments the mean log GR per treatment group showed a negative correlation (r=-0.87) with log[F-Nucl]. The most effective non-toxic treatments were 25 mg/kg over 5 or 24 h; the i.a. route was superior to i.v. on the basis of [FU+F-Nucl], RI, the reduction in log GR, and Kaplan-Meier survival statistics. For liver and kidney Tot. F (>83% FU catabolites) reached ca. 3-4 and 6-7 micromol/g, respectively, at the highest dose rates for either route; F-Nucl were detected only for Tot. F>500 nmol/g and increased exponentially as Tot. F increased (toxic treatments). The concentrations of the main catabolite (alpha-fluoro-beta-alanine, FBAL) in tumor did not correlate with Tot. F but rather with FBAL levels in kidney (r=0.90, all treatments), indicating that uptake of liver-derived FBAL from the circulation is the major source of FBAL in tumor.     

Effect of lower-body positive pressure on postural fluid shifts in men

Summary To quantify the effect of 60 mm Hg lower-body positive pressure (LBPP) on orthostatic blood-volume shifts, the mass densities (±0.1 g· l^–1) of antecubital venous blood and plasma were measured in five men (27–42 years) during combined tilt table/antigravity suit inflation and deflation experiments. The densities of erythrocytes, whole-body blood, and of the shifted fluid were computed and the magnitude of fluid and protein shifts were calculated during head-up tilt (60°) with and without application of LBPP. During 30-min head-up tilt with LBPP, blood density (BD) and plasma density (PD) increased by 1.6±0.3 g · l^–1, and by 0.8±0.2 g · l^–1 (±SD) (N=9), respectively. In the subsequent period of tilt without LBPP, BD and PD increased further to +3.6±0.9 g · l^–1, and to +2.0±0.7 g · l^–1 (N=7) compared to supine control. The density increases in both periods were significant (p<0.05). Erythrocyte density remained unaltered with changes in body position and pressure suit inflation/deflation. Calculated shifted-fluid densities (FD) during tilt with LBPP (1006.0±1.1 g · l^–1,N=9), and for subsequent tilt after deflation (1002.8±4.1 g · l^–1,N=7) were different from each other (p<0.03). The plasma volume decreased by 6.0±1.2% in the tilt-LBPP period, and by an additional 6.4±2.7% of the supine control level in the subsequent postdeflation tilt period. The corresponding blood volume changes were 3.7±0.7% (p<0.01), and 3.5±2.1% (p<0.05), respectively. Thus, about half of the postural hemoconcentration occurring during passive head-up tilt was prevented by application of 60 mm Hg LBPP.H. Hinghofer-Szalkay was a European Space Agency fellow on leave from the Physiological Institute, Karl-Franzens-University, A-8010 Graz, Austria.     

Histochemical demonstration of endogenous estrogen in breast carcinomas: Biochemical and clinical correlation

Summary In a study of 277 patients with breast carcinomas, the PAP immunoperoxidase method for demonstrating endogenous estrogen was correlated with the sucrose density gradient (SDG) assay and with histologic and clinical features. The results from the PAP method and SDG assay agreed in 59 of 84 patients (82.1%) on whom both methods were performed. Histologically, the PAP method was positive in 7 of 7 patients with non-invasive carcinomas, in 164 of 233 patients (70.4%) with common invasive ductal carcinoma, and in 21 of 22 of those with special histological types of invasive carcinomas not including Paget's disease, medullary or apocrine carcinoma, where only 5 of 14 were positive. Clinically, 15 of 18 patients with positive endogenous estrogen showed a response to endocrine therapy as opposed to 1 of 9 patients with a negative endogenous estrogen. The mean survival was 31.2 and 15.6 months, respectively for patients with positive and negative endogenous estrogen. Remission for longer than 2 years was seen more often in patients with positive endogenous estrogen. These results suggest a clinical utility of the present PAP method which, therefore, deserves a further trial as an alternative to histochemical methods aiming at the estrogen receptors.This work was supported by Grants-in Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (No. 56480119).This paper was presented at the 72nd Annual Meeding of International Academy of Pathology (United States-Canadian Division), Atlanta, Georgia, March 1, 1983.     

The adaptation of the plaque reduction assay for measuring specific cytotoxic cells in limiting dilution cultures

The use of the original haemolytic plaque reduction technique to measure cytotoxic T lymphocytes (CTL) has been developed further as a rapid screening assay, particularly suitable for limiting dilution analyses. Using hybridoma cells as targets, the cytotoxicity has been measured by the loss of haemolytic plaque formation and by the reduction of the amount of haemolytic monoclonal antibody secreted from viable target cells into the assay supernatants. The assessment of large numbers of cytotoxic samples has been greatly facilitated by quantitating the amount of haemoglobin released in the assay with an automated microELISA multiscanner and by scoring visually using a modification of the spot test. Using these new techniques, relatively high frequency estimates of cytotoxic cell precursors in an allogeneic response (1 in 462 spleen cells) and an anti-fluorescein response (1 in 3970 spleen cells) were obtained.     

Digital subtraction angiography (DSA): New perspectives in angiography

Summary Digital subtraction angiography (DSA) has strongly influenced angiographic procedures. Because it is less invasive it has increased the total number of angiographies in all places where it was introduced. The paper gives an introduction to the procedure explaining the roles of digital and subtraction in DSA. It is written from a technical point of view. The examples are taken from and with the DVI system.     

Spread of epidural analgesia following a constant pressure injection

(1) The spread of epidural analgesia following injection of 15ml of 2% mepivacaine was 17.3 ± 0.6, 14.3 ± 0.4, and 13.3 ± 0.7 spinal segments in cervical, thoracic, and lumbar epidural analgesia, respectively. The patients age showed significant correlation with the spread of epidural analgesia in cervical (r = 0.5776, p < 0.001), thoracic (r = 0.3758, p < 0.01), and lumbar area (r = 0.8195, p < 0.001). The spread of cervical epidural analgesia was more caudad than cephalad (p < 0.05), but in lumbar epidural analgesia it was more cephalad than caudad (p < 0.05). There was no difference between the cephalad and caudad spread in thoracic epidural analgesia.(2) The epidural pressure immediately after injection of 15ml of 2% mepivacaine into the lumbar epidural space at a constant pressure (80mmHg) correlated to the patients age (r = –0.5714, p < 0.001) and the spread of analgesia (r = –0.3904, p < 0.05). The lower epidural pressure associated with higher age, the wider spread of analgesia. There was no significant correlation between the residual pressure at 60 seconds and the age or the spread of analgesia.(Hirabayashi Y et al.: Spread of epidural analgesia following a constant pressure injection: an investigation of relationships between locus of injection, epidural pressure and spread of analgesia. J Anesth 1: 44–50, 1987)     

In Vivo Observation of Cutaneous Larva Migrans by Fluorescence-Advanced Videodermatoscopy

Fluorescence-advanced videodermatoscopy is not a widespread diagnostic technique. Its application in dermatology can facilitate the diagnosis of diseases such as cutaneous larva migrans by enabling us to recognize the precise position of larva in vivo on the skin. Using this noninvasive technique, we detected a case of cutaneous larva migrans in a patient.     

Discrepancies Between Australian Eating Disorder Clinicians and Consumers Regarding Essential Components of Dietetic Treatment

BackgroundA recent Delphi study indicated that, compared with eating disorder (ED) consumers and carers, ED specialists were less likely to endorse involvement of a dietitian as a standard component of treatment. In addition, there was disagreement between these groups regarding the inclusion of a number of components of dietetic treatment.ObjectiveThis study aimed to further investigate these data to identify areas of disagreement among ED specialist dietitians, ED specialist non–dietetic clinicians, consumers, and carers with regard to outpatient dietetic treatment.Design and participants/settingThe ED specialists panel from a previous Delphi study was recoded into 2 panels: ED specialist dietitians (n = 31) and ED specialist non–dietetic clinicians (n = 48) to compare responses of these panels with responses from consumers (n = 32) and carers (n = 23).Main outcome measuresStatements in 7 categories relating to referral to dietitian, essential components of outpatient dietetic treatment regarding 4 ED patient populations, strategies to promote multidisciplinary collaboration, and skills dietitians should possess if treating patients with an ED were rated on a 5-point Likert scale.Statistical analysis performedOne-way analysis of variance was conducted with post-hoc multiple comparisons to compare mean statement ratings.ResultsThirty-seven statements (30%) showed statistically significant differences (P < .05) in responses between panels. Discrepancies were primarily observed for statements regarding how and when dietetics is included in treatment and essential components of dietetic treatment, particularly the use of behavioral tasks, such meal plans and self-monitoring. Results also highlighted deficits in participants’ understanding of core responsibilities of dietitians in ED treatment and dietitians “drifting” from delivering evidence-based components of dietetic treatment.ConclusionsResults of this study show discrepancies among ED dietitians, clinicians, consumers, and carers regarding what dietetic treatment for people with EDs should encompass. It also indicates the need for further research into optimizing dietetic treatment for EDs that is conducted in collaboration with individuals with lived experience.     

舌癌术前化疗PCNA、bcl-2、Bax基因表达及临床意义

目的 :通过舌癌术前化疗增殖细胞核抗原 (PCNA )和细胞凋亡相关基因 bcl- 2、Bax表达的研究 ,探讨舌癌的化疗作用机制。 方法 :对舌乳头状瘤、舌癌和舌癌术前化疗标本共 34例 ,采用免疫组织化学染色技术——酶标链亲和素生物素法 (L SAB)染色并进行光镜下观察。结果:PCNA在舌癌中的表达最强 ,在舌癌术前化疗中的表达明显减弱 (P <0 .0 5 ) ,其与舌乳头状瘤表达相似 (P >0 .0 5 )。 bcl- 2在舌癌术前化疗及舌乳头状瘤中低表达(P >0 .0 5 ) ,舌癌中表达明显增强 (P <0 .0 5 )。Bax在舌癌组和乳头状瘤组中表达有明显差异 (P <0 .0 5 )。结论 :化疗药物抑制肿瘤生长的机制可能与抑制肿瘤细胞增殖和诱导肿瘤细胞程序性死亡有关 ,提示舌癌术前化疗对肿瘤的预后有重要意义。