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Inducible repair and the two forms of tumour hypoxia--time for a paradigm shift.

Clinical experience shows that there is a therapeutic window between 60 and 70 Gy where many tumours are eradicated, but the function of the adjacent normal tissues is preserved. This implies much more cell kill in the tumour than is acceptable in the normal tissue. An SF2 of 0.5 or lower is needed to account for the eradication of all tumour cells, while an SF2 of 0.8 or higher is needed to explain why these doses are tolerated by normal tissues. No such systematic difference is known between the intrinsic sensitivity of well-oxygenated normal and tumour cells. The presence of radioresistant hypoxic cells in tumours makes it even more difficult to understand the clinical success. However, there is experimental evidence that starved cells lose their repair competence as a result of the depletion of cellular energy charge. MRS studies have shown that low ATP levels are a characteristic feature of solid tumours in rodents and man. In this paper we incorporate the concept of repair incompetence in starving, chronically hypoxic cells. The increased sensitivity of such cells has been derived from an analysis of mammalian cell lines showing inducible repair. It is proportional to the SF2 and highest in resistant cells. The distinction between acutely hypoxic radioresistant cells and chronically hypoxic radiosensitive cells provides the key to the realistic modelling of successful radiotherapy. It also opens new conceptual approaches to radiotherapy. We conclude that it is essential to distinguish between these two kinds of hypoxic cells in predictive assays and models.

Cell Hypoxia↗

Proteomics: a paradigm shift.

Proteome--the protein complement of a genome--has become the protein renaissance and a key research tool in the post-genomic era. The basic technology involves the routine usage of gel electrophoresis and spectrometry procedures for deciphering the primary protein sequence/structure as well as knowing certain unique post-translational modifications that a particular protein has undergone to perform a specific function in the cell. However, the recent advancements in protein analysis have ushered this science to provide deeper, bigger and more valuable perspectives regarding performance of subtle protein-protein interactions. Applications of this branch of molecular biology are as vast as the subject is and include clinical diagnostics, pharmaceutical and biotechnological industries. The 21st century hails the use of products, procedures and advancements of this science as finer touches required for the grooming of fast-paced technology.

Animals↗

Capturing the paradigm shift in HIV treatment: changing attitudes in the choice of combination antiretroviral drugs by high HIV caseload Australian GPs (1996-1997).

The use of combination antiretroviral therapy for HIV infection is a rapidly changing field. To assess the impact of recent studies on prescribing patterns, two surveys of 21 high HIV caseload Australian GPs were undertaken in June 1996 and June 1997 to plot changes in the choice of combination antiviral therapy. Of the 17 GPs who responded to the survey in each year, the number of HIV-infected patients seen at their practices were estimated to be 5,061 in 1996 and 5,912 in 1997. In 1996, 40% of their patients were estimated to be on antiretroviral therapy compared to 60% in 1997 (p < 0.05). In 1996, most GPs preferred using dual combination therapy (59%); whereas in 1997, triple combination therapy was preferred (82%). Between 1996 and 1997, there was a significant change by high caseload Australian GPs in the choice of antiretroviral drugs with many combinations being preferred prior to presentation of efficacy data for those combinations, or recommendation through national guidelines.

Anti-HIV Agents↗

A paradigm shift in the evaluation of information technology in health care.

This paper examines the notion of productivity, which underlies the reorganization of Quebec's health care system around an information technology-driven virage ambulatoire, or shift to ambulatory (outpatient) care. The reorganization may be traced to a policy decision to address the health care's productivity crisis, a crisis diagnosed in the 1970s based on macroeconomic expenditure trend lines highlighting the "obstacle" to economic growth and to balanced budgets. The information technology-driven virage ambulatoire is aimed at a structural reorganization, based on the principle of: boosting productivity in a service- or information-based economy. The State, thus, relied on analytic categories developed for a particular mode of economic analysis to lead a hospital restructuring program oriented around information technology-based ambulatory care. The result was a refocus from clinical and therapeutic efficiency to administrative imperatives of time, cost, and optimization. Hence, Québec moved to neoliberal productivist system in which clinical and therapeutic effectiveness are subordinated to economic imperatives.

Delivery of Health Care↗

Is it time for a paradigm shift? Is erythropoietin deficiency still the main cause of renal anaemia?

An increasing number of reports documenting resistance to human recombinant erythropoietin (rHuEPO) therapy are challenging the concept that erythropoietin deficiency is the main cause of the anaemia of chronic kidney disease (CKD). In an attempt to establish whether other factors play a more predominant role in the anaemia of CKD, 988 patients receiving dialysis were assessed for a wide range of variables. Data were collected on haematocrit (Hct) levels, rHuEPO dose, dry weight, serum ferritin, transferrin saturation, serum albumin, serum aluminium, serum parathyroid hormone intact, eKt/V for urea, gender, dose of i.v. iron administered, time in hospital, and use of i.v. vancomycin. Hyporesponsiveness to rHuEPO was defined as patients requiring >500 IU/kg/week or failing to achieve Hct levels of >30%. Ninety-two (9.2%) of the 988 patients met the above criteria for hyporesponsiveness to rHuEPO. In 21 of these patients, Hct concentrations remained <30% at 6-month follow-up. There were known haematological causes of refractoriness to rHuEPO in nine of these patients. During extended follow-up, probable causes of hyporesponsiveness were discovered in all but two of the remaining 13 patients. Of 62 dialysis patients who received rHuEPO at doses >500 IU/kg/week, 45 (73%) had Hct concentrations of 33-42%. These patients were responding to the higher doses of rHuEPO with no obvious adverse effects. Lower values of serum ferritin, transferrin saturation, and eKt/V, or higher levels of parathyroid hormone or serum aluminium were not associated with higher rHuEPO dose requirements. These results suggest that erythropoietin deficiency is still the main cause of the anaemia of CKD. Erythropoietin replacement therapy can correct the anaemia in almost all iron replete patients providing enough hormone is given, functional iron deficiency is avoided, aluminium levels and parathyroid toxicities are controlled and that no de novo haematological condition that affects erythropoiesis or red blood cell survival develops. Consideration should be given to modifying the definition of rHuEPO hyporesponsiveness. The US Hct target of 33-36% for haemodialysis patients is narrow and the European target of Hct >33% may be significantly more practical and physiologically relevant.

Adult↗

Radical resection of vulvar malignancies: a paradigm shift in surgical approaches.

Significant changes have occurred over the past two decades in the management of vulvar cancer. The most important changes have been the individualization of care for all patients, and the introduction of a multidisciplinary team approach. Radiation has been progressively incorporated into treatment protocols, and more recently chemoradiation has been investigated.

Female↗