Immunocryosurgery for basal cell carcinoma: results of a pilot, prospective, open-label study of cryosurgery during continued imiquimod application

Background/aim  Theoretical considerations support the combination of cryosurgery and topical imiquimod to treat basal cell carcinomas (BCC). The aim of the present study was to test the feasibility and efficacy of 'cryosurgery during continued imiquimod application' ('immunocryosurgery') to treat 'high-risk-for-recurrence' BCCs.
Methods  Thirteen patients with 21 biopsy-proven tumours (4 of 21 relapses after prior surgery) were included. After 2–5 weeks (median, 3) of daily 5% imiquimod cream application, the tumours were treated by liquid N₂ cryosurgery (spray, two cycles, 10–20 s) and imiquimod was continued for additional 2–12 weeks (median, 4). The outcome after at least 18 months of follow-up (18–24 months) is currently reported.
Results  Nineteen of 21 tumours responded promptly to immunocryosurgery; two tumours required additional treatment cycles to clear. Thus, the clinical clearance rate was 100%. Only 1 of 21(5%) tumour relapsed after at least 18 months of follow-up (cumulative efficacy: 95%).
Conclusions  'Immunocryosurgery' is a promising non-surgical combination modality to treat 'high-risk-for-recurrence BCCs'. Initial evidence is suggestive of an at least additive effect of the two combined modalities. Further studies comparing immunocryosurgery directly with cryosurgery and imiquimod monotherapies will confirm the reported results.     

Service profiles of general practitioners in Europe. European GP Task Profile Study.

BACKGROUND: General practice is the focal point of primary care. There are national differences in the structure and organization of practice, the relationship with secondary care is being redefined, and in some countries major changes are taking place. AIM: To describe and examine differences in the service profiles of general practitioners (GPs) in European countries. METHOD: Standardized questionnaires in the national languages were sent to samples of GPs in 1993. Four areas of service provision were measured: the GP's position in the first contact with selected health problems, the involvement in minor surgery and the application of medical procedures, disease management and preventive care. The importance of the gatekeeping role, remuneration system, and geographical region in Europe was examined by comparing scores in appropriate national groupings. RESULTS: Data were received from 7233 GPs in 30 countries. Most national samples were random and the average response rate was 47%. In countries where GPs have a gatekeeping role, they had a relatively stronger position as doctors of first contact. In those countries where GPs were usually self-employed, they had a stronger role in disease management and screening for blood cholesterol. In the examination of the three structural elements of health care, the most striking differences were evident in the comparison between eastern and western Europe. GPs throughout Europe had a comparatively small role in organized health education. CONCLUSION: The position of GPs is weak in eastern Europe and some Mediterranean countries, where service profiles have a limited range. General practice was more comprehensive where the doctors had a gatekeeping role.     

Research into the results of resection of hilar bile duct cancer

We found mentions of 581 resections of hilar bile duct cancer in the literature to January 1989. Resection in 499 patients, reported or updated since 1980, resulted in an operative mortality of 12% and a 5-year survival rate of 13%. Resections confined to the hepatic duct confluence or extended to the quadrate lobe led to an 8% operative mortality and a 7% 5-year survival rate, although resections combined with major liver resection gave a 15% operative mortality and a 17% 5-year survival rate. Despite the best treatments available, present-day resection modalities are usually still not radical. Extension of resection in the retrohilar and hepatoduodenal direction might further improve the long-term surgical results.     

Comparative expression profiling in primary and immortalized endothelial cells: changes in gene expression in response to hydroxy methylglutaryl-coenzyme A reductase inhibition.

Immortalized cell lines offer significant logistical advantages over primary cells when used for in-vitro studies. Immortalized cells may, however, exhibit important differences relative to their primary cell counterparts. In this study, microarrays were used to make a genome-wide comparison between primary human umbilical vein endothelial cells (HUVECs) and EA.hy926, an immortalized HUVEC cell line, in their baseline properties and in their response to inhibition of the mevalonate pathway with an inhibitor of hydroxy methylglutaryl-coenzyme A reductase (statin). HUVECs and EA.hy926 were incubated with control medium, atorvastatin, mevalonate, or a combination of atorvastatin and mevalonate for 24 h. Gene expression profiles were obtained in duplicates using Affymetrix Human Genome U133A 2.0 arrays (Santa Clara, California, USA). Probe-sets were selected according to the following criteria: a twofold or greater increase/decrease in atorvastatin-treated cells compared with untreated cells; a twofold or greater reversal of the effect of atorvastatin by combined treatment with atorvastatin and mevalonate; no significant change in gene expression in cells treated with mevalonate alone compared with untreated cells. Most genes that were expressed by untreated HUVECs, were also expressed by untreated EA.hy926 cells. EA.hy926 cells, however, constitutively expressed a large number of additional genes, many of which were related to cell cycle control and apoptosis. Atorvastatin induced differential expression (> or = twofold) of 103 genes in HUVECs (10 up, 93 down) and 466 genes in EA.hy926 cells (198 up, 268 down). Applying the above selection criteria, thrombomodulin and tissue plasminogen activator were up-regulated in both cell types, whereas, connective tissue growth factor, thrombospondin-1, and cysteine-rich angiogenic inducer 61 were down-regulated. In conclusion, EA.hy926 cells retain most of the characteristics of endothelial cells under baseline conditions as well as after treatment with atorvastatin. It is necessary, however, to carefully select and validate changes in genes that are the focus of studies when using EA.hy926 cells. While this cell line is highly useful in studies on some genes, including genes encoding molecules involved in regulating thrombohemorrhagic homeostasis, they appear to be less suited for studies focused on other genes, particularly those involved in the regulation of cell proliferation and apoptosis.     

Local housing scheme and political preference as conditions for the results of a health centre-stimulating policy in The Netherlands.

About two decades ago, changes in the demand for primary care in the Netherlands resulted in a need for more interprofessional collaboration. Health centres developed as a new supply of integrated care. The government was aware of the importance of this phenomenon in its policy to strengthen primary care. The encouragement of health centres was a crucial part of it. The development of this policy and the resulting growth in the number of health centres will be reviewed here. In general, this growth is lagging behind initial policy expectations, partly because of a lack of instruments to implement PHC policy. Examination of geographical distribution of health centres, however, shows a variation suggesting that local factors also affect the development of health centres. Empirical findings show that the number of newly built houses in an area and the political 'colour' of the alderman for public health play a role in the development of health centres and thus co-determine the results of a central promotion policy to a certain extent.     

Increased salt retention and hypertension from non-steroidal agents in the elderly

We studied blood pressure and natriuretic responses to acute salt loading, and the effect of non-steroidal anti-inflammatory agents on these responses, in five healthy normotensive women aged 65 to 71 years. Five women aged 25 to 31 years acted as controls. Intravenous saline loading, with and without prior ingestion of ibuprofen, was 15 ml/kg/h for 3 h. Baseline blood pressures were higher in the elderly. Saline infusion without ibuprofen raised systolic blood pressure (SBP) by about 25 mmHg in the older group only. Ibuprofen increased baseline SBP in the elderly (129 +/- 6 vs. 116 +/- 5 mmHg, p < 0.05). Saline loading after ibuprofen again raised blood pressure by about 25 mmHg in the elderly only. The elderly group showed markedly increased sodium excretion during saline loading, but this was reduced by ibuprofen. Ibuprofen had no effect on SBP or sodium excretion in controls. Ageing appears to increase susceptibility to salt retention and hypertension from non-steroidal anti-inflammatory agents.      

Uroscopy in the 21st century: high-field NMR spectroscopy

From the experiments described, it can be seen that there are different research approaches that can be taken and these are summarized in Table 1. Whereas much scientific research is principally hypothesis led, there remains, nevertheless, an important place for exploratory research. High resolution NMR can measure, directly and simultaneously, a wide range of endogenous metabolites in biological fluids and has the unique capability of providing structural information on the metabolites detected. It has proved to be a powerful research tool with which to study inherited metabolic diseases, renal disease, drug metabolism, and toxicity, and can be used to monitor the effects of drug therapy. For instance, by using a library of experimental toxins one can map the metabolic profile of site-specific nephron injury. With this approach in man one could eventually take an unknown disease such as Balkan nephropathy and predict the initial site of tubular injury, the mode of injury and therefore the kind of toxin capable of producing that injury. NMR spectroscopic techniques are still advancing rapidly, with ever increasing sensitivity and sophistication of NMR pulse sequences to enhance structural elucidation in complex mixtures. Given the advances in directly coupled HPLC-NMR and even HPLC-NMR-mass spectroscopy it is likely that these technologies in conjunction with pattern recognition will make major contribution to our understanding of renal processes and provide new diagnostic insights in the 21st century.      

Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions

Autosomal dominant cerebellar ataxia with progressive macular degeneration is caused by a CAG/glutamine repeat expansion in the SCA7 gene/protein. Neuronal intranuclear inclusions were detected in the brain of an early onset SCA7 case with the 1C2 antibody directed against an expanded polyglutamine domain. Nuclear inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7. They were also observed in other brain regions, including the cerebral cortex, not considered to be affected in the disease. Using confocal microscopy we showed that some inclusions were ubiquitinated, but to varying degrees, ranging from <1% in the cerebral cortex to 60% in the inferior olive. In addition, we also observed cytoplasmic staining using the 1C2 antibody, particularly in the supramarginal gyrus, the hippocampus, the thalamus, the lateral geniculate body and the pontine nuclei. These data confirm that the presence of intranuclear inclusions in neurons is a common characteristic of disorders caused by CAG/polyglutamine expansions, but unlike what has been reported for Huntington's disease, SCA1 and SCA3/MJD, in SCA7 the inclusions were not restricted to the sites of severe neuronal loss.      

A model for the evaluation of search queries in medical bibliographic sources

The aim of this study was to develop a model to evaluate the retrieval quality of search queries performed by Dutch general practitioners using the printed Index Medicus, MEDLINE on CD-ROM, and MEDLINE through GRATEFUL MED. Four search queries related to general practice were formulated for a continuing medical education course in literature searching. The selected potential relevant citations from the course instructor and the 103 course participants together served as the basic set for the three judges to evaluate for (a) relevance and (b) quality, with the latter based on journal ranking, research design and publication type. Relevant individual citations received a citation quality score from 1 (low) to 4 (high). The overall search quality was expressed in a formula, which included the individual citation quality score of the selected and missed relevant citations, and the number of selected non-relevant citations. The outcome measures were the number and quality of relevant citations and agreement between the judges. Out of 864 citations, 139 were assessed as relevant, of which 44 citations received an individual citation quality score of 1, 76 of 2, 19 of 3 and none of 4. The level of agreement between the judges was 68% for the relevant citations, and 88% for the non-relevant citations. We describe a model for the evaluation of search queries based not only on the relevance, but also on the quality of the citations retrieved. With adaptation, this model could be generalized to other professional users, and to other bibliographic sources.