The effect of individual radiographers on rates of attendance to breast screening: a 7-year retrospective study.

AIM: To establish whether individual radiographers had significantly different rescreening rates whilst controlling for other known confounding factors. MATERIALS AND METHODS: Women aged 50-69 years were identified from a state-wide screening database at their first screening attendance during the study period (2007-2013). The radiographer performing this index screen and potential confounding factors were recorded and subsequent screening behaviour was assessed. Clients with abnormal screens and those known to have died during the time period were excluded. A univariate analysis of the data from 160,028 women was assessed using the chi-square test to compare those women who attended their next mammography with non-re-attenders. Logistic regression was used to calculate the likelihood of "re-attendance success" across a range of variables. The probability of re-attendance for 11 randomly selected radiographers was determined from the logistic regression model, whilst controlling for other variables. RESULTS: Comparison of non-re-attenders (n=49,698) with 110,330 (69%) women attending the next round of screening revealed significant differences, including radiographer (Wald statistics=1188, p<0.000) even when all other known factors were controlled. CONCLUSION: This large, population-level study demonstrates that individual radiographer factors appear to influence a women's decision to return for their next screening round. Further research is required to identify reasons for differing rescreen rates and provide education and retraining of individual radiographers as appropriate.

Public versus private hospital maternity length of stay: a gamma mixture modelling approach.

Application of a gamma mixture model to obstetrical diagnosis-related groups (DRGs) revealed heterogeneity of maternity length of stay (LOS). The proportion of long-stay subgroups identified, which can account for 30% of admissions, varied between DRGs. The burden of long-stay patients borne was estimated to be much higher in private hospitals than public hospitals for normal delivery, but vice versa for Caesarean section. Such differences highlights the impact of DRG-based casemix funding on inpatient LOS and have significant implications for health insurance companies to integrate casemix funding across the public and private sectors. The analysis also benefits hospital administrators and managers to budget expenditures accordingly.

The Quality of Surgical Care Project: benchmark standards of open resection for abdominal aortic aneurysm in Western Australia.

BACKGROUND: The Quality of Surgical Care Project (QSCP) was established in May 1996, to evaluate surgical outcomes and where indicated, recommend changes to improve the quality of surgical care in Western Australia (WA). The purpose of this study is to establish benchmark standards in WA for operative mortality, 5-year survival and length of stay in all patients who were surgically treated for aneurysm of the abdominal aorta (AAA) in WA. METHODS: The WA Linked Database was used to link the morbidity and mortality records of all patients admitted and surgically treated for AAA in WA from 1985 to 1994. The linked chains of de-identified hospital morbidity and death records were selected using diagnostic and procedure codes pertaining to AAA. Three groups were separated for analysis: those admitted for rupture, those admitted for elective repair, and those who were admitted to hospital as an emergency without mention of rupture but who underwent repair for AAA. Independent analysis for gender and patients 80 years or more were included in the study. Patients were excluded from the study if they were less than 55 years of age. RESULTS: A total of 1475 cases (1257 males, 218 females) were identified. The mean age in elective cases was 70.4 years in males and 72.4 years in females, and for rupture the mean ages were 71.9 and 74.8 years, respectively. Median length of stay for males was 12 days for elective cases. Admission type or age did not significantly influence length of stay. Thirty-day mortality in males was 4.4% for elective repair and 36.7% for ruptured AAA and 5-year survival was 71.7 and 47.7%, respectively. The overall case fatality rate for ruptured AAA was 79.3% which included those cases who died from rupture without being admitted to hospital. CONCLUSIONS: These community-wide data provide a realistic measure of surgical performance for open repair of AAA. The outcomes for elective and rupture repair for AAA compare favourably with standards reported by international centres of excellence. They also support the use of this procedure in patients over 80 years of age with rupture. This information can be used for ongoing audit purposes and as a benchmark for the introduction of new treatment modalities.

A review of hospital medical record audits: implications for funding and training.

This paper summarises the findings of coding audits in seven hospitals and one re-audit conducted by the Health Department of Western Australia. The accuracy of the coding in the first audits, as measured by differences in AN-DRG assignment, varied from 83% to 93%. The accuracy of the coding in the re-audited hospital increased by 6% to 94.5%. The major coding problems related to incorrect abstraction of information from the medical record, inaccurate code assignment, non-application of the Australian Coding Standards, or poor documentation. On average, these coding problems resulted in a loss of nearly $400,000 per hospital per year in the surveyed hospitals.

Hospitalisation of the elderly during the last year of life: an application of record linkage in Western Australia 1985-1994.

STUDY OBJECTIVE: To measure the trend, pattern, and cost of time spent in hospital during the last year of life in Western Australia and to identify trends in the place of death. The results were compared with those reported from the Oxford Record Linkage Study. DESIGN: Mortality records for those aged 65 years and over were linked to inpatient hospital morbidity records with a date of separation within one year before death. Comparative inpatient resource utilisation was estimated using ANDRG 3.0 cost weights for Australian public hospitals. SETTING: Western Australia. PARTICIPANTS: All 68,875 persons aged 65 years and over who died between 1 January 1985 and 31 December 1994. MAIN RESULTS: Increasing proportions of all age groups (65-74, 75-84, and 85+ years) were admitted to hospital at least once in the year before death during 1985-94, but the chance of admission decreased with age. There was a trend towards a greater number of shorter admissions per person. Total bed days per person showed no significant increase, except at ages 65-74 years. Total inpatient resource utilisation during the last year of life was lowest and remained constant in those aged 85 years and over, while increasing gradually (3.7% per annum) in the younger elderly. The Western Australian population spent more time in hospital in the last year of life at ages 65-74 years, but the advanced elderly spent less time in hospital, when compared with the Oxford Region. CONCLUSIONS: Recent gains in life expectancy and higher per capita health expenditure have not been accompanied by more time spent in hospital during the last year of life at ages 75+ years. International differences between Western Australia and Oxford can be explained by differences in aged care provision.

Immunohistochemical characterisation of immunological changes at the tumour site after chemo-immunotherapy with doxorubicin, interleukin-2 and interferon-gamma.

Chemo-immunotherapy for the treatment of cancer, whilst promising from a preclinical and clinical perspective, remains limited by a lack of clear understanding of the in vivo antitumour mechanisms of this multi modality strategy. There is now strong evidence that systemic immunological parameters do not correlate with therapeutic activity. In contrast, information on therapy related immunological change at the tumour site is scarce. Having previously demonstrated that the therapeutic activity of doxorubicin chemotherapy can be significantly augmented by the co-administration of two cytokines, interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), the objective of the present study was to investigate the mechanism of action of this enhanced therapeutic activity by characterising the effect of single, double and triple agent therapy upon local tumour immune parameters. Twenty-four hours after the administration of treatment to WAG rats bearing solid tumour implants of a colonic adenocarcinoma, the extent of tumour infiltration in response to the therapy was assessed in haematoxylin and eosin stained tumour sections. Treatment with doxorubicin/IL-2/IFN-gamma or IL-2/IFN-gamma was associated with a marked augmentation of the size of the tumour infiltrate (P < 0.001), as compared to untreated tumours or to those treated with any other single or double agent combination. Phenotypic evaluation of the tumour infiltrate using immunoperoxidase stained tumour sections revealed that a considerable proportion of the infiltrating cells were T cells and macrophages, whilst B cells were not detected in significant numbers. Although this phenotypic profile was not qualitatively influenced by therapy, marked quantitative differences were observed. Most notably, tumours treated with either doxorubicin/IL-2/IFN-gamma or IL-2/IFN-gamma exhibited a significant increase in the numbers of CD25+ infiltrating cells (P < 0.001). These changes in the tumour immunological response closely paralleled the therapeutic responses described previously. Thus, the enhanced therapeutic activity of the triple agent regimen may result from a profound augmentation of the size of the tumour infiltrate, together with a similar increase in the numbers of activated infiltrating cells. This study supports the concept that the immune response within the tumour is the appropriate site for investigations into the immunological antitumour mechanisms of immunotherapy and chemo-immunotherapy.

A comparative study of the anticancer efficacy of doxorubicin carrying microspheres and liposomes using a rat liver tumour model.

Due to low efficacy of chemotherapy in the treatment of liver cancer, several methods of drug targeting have been investigated. Liposomes designed to carry cytotoxic drugs to the liver are currently under clinical evaluation. While experimental evidence shows promise, this method of drug delivery has several disadvantages that include short shelf life and poor drug delivery into tumour tissue. An alternative strategy for targeted drug delivery involving use of ion exchange microspheres may overcome these limitations while still reducing systemic toxicity and maintaining therapeutic efficacy. The purpose of this study was to determine the relative antitumour efficacy of these two drugs carrying systems in the treatment of liver cancer. Compared to controls, DOX treatment with free drug, liposomes or microspheres significantly reduced tumour growth by 56% (P < 0.001), 51% (P < 0.01) and 79% (P < 0.001) respectively. Furthermore, the DOX-microsphere treatment was significantly better than either of the other DOX treatments (53%, P < 0.05) or the sham-microsphere treated group (64%, P < 0.05). Thus, drug microspheres can increase the anti-tumour efficacy compared to either free or liposomal drug while simultaneously reducing systemic toxicity.

Prevention of myelosuppression does not improve the therapeutic efficacy of chemo-immunotherapy.

This study was designed to investigate whether the prevention of doxorubicin (DOX) induced myelosuppression could further improve the therapeutic efficacy of chemoimmunotherapy with DOX, interleukin-2 (IL-2) and interferon gamma (IFN-gamma). The antitumour activity of systemic IL-2/IFN-gamma immunotherapy in combination with DOX administered either systemically, regionally or on ion-exchange microspheres, was assessed in WAG rats bearing hind limb solid colonic adenocarcinoma implants. Whilst the use of microspheres to transport DOX clearly avoided the myelosuppression, systemic and renal toxicity associated with the use of free DOX, it did not provide any therapeutic advantage over chemo-immunotherapy with free systemic or regional drug.

Improved efficacy of doxorubicin by simultaneous treatment with interferon-gamma and interleukin-2.

Doxorubicin (DOX) is a potent anticancer agent active against a wide range of human neoplasms, yet, as is characteristic of most chemotherapeutics, the treatment of cancer with DOX alone has met with only limited success. This study was designed to investigate the possibility that the therapeutic potential of DOX could be enhanced by combination with one or more biological response modifiers. Segments (1mm3) of a transplantable colonic adenocarcinoma were implanted into the hind limbs of male WAG rats (200-250g). Serial tumour measurements were taken 3 x weekly throughout the 4 week experimental period by measuring the longest and perpendicular lengths with calibrated calipers. All drug administration was via a chronic indwelling jugular catheter, commencing 12 days after tumour implant, with control animals receiving physiological saline. Treatment of animals with DOX (4.5mg/kg as a 15 minute i.v. infusion), interferon gamma (IFN-gamma) (5 x 10(5) U/kg/day bolus i.v. for 5 days) or interleukin-2 (IL-2) (1 x 10(5)U/rat/day continuous i.v. infusion for 5 days) retarded tumour growth by approximately 30% by the completion of the study period (P < 0.001). The combined administration of IFN-gamma with DOX did not significantly alter the antitumour activity of either DOX or IFN-gamma. Concurrent administration of IL-2 with DOX also showed this treatment to have no therapeutic activity over that achievable with either agent alone. However, treatment of animals with IL-2, IFN-gamma and DOX resulted in a significant increase in tumour growth inhibition compared to DOX with either single cytokine (P < 0.001) and this was achieved without any apparent increases in the gross toxicity of DOX.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro and in vivo responses of doxorubicin ion exchange microspheres to hyperthermia.

The utility of microspheres as targeted drug delivery agents is addressed with reference to using heat during formulation and to administration in combination with hyperthermia. It was demonstrated that rate of loading of the drug doxorubicin onto resin microspheres is enhanced under conditions of elevated temperature but this was shown to increase the incidence of microsphere aggregation. Total amount of drug loaded was related to time rather than temperature such that low temperature loading for up to 24 h produced optimum quality injectates. However, release of doxorubicin from microspheres was significantly increased during elevations of temperature to 43 degrees C. Thus, during hyperthermia doxorubicin release can be increased to provide periods of high drug availability targeted to tumour tissue for concomitant thermochemotherapy with microspheres. The therapeutic benefit derived from this combined therapy was assessed in 20 rabbits with VX2 carcinoma implanted in the liver. Hyperthermia was delivered by 2450 MHz microwave applicator to the exteriorized liver at 43 degrees C for 30 min, while chemotherapy was administered by intratumoural injection of doxorubicin microspheres (2.3 mg) into each tumour. Both hyperthermia and chemotherapy alone significantly reduced the size of tumours 10 days following treatment (p less than 0.01). However, in animals treated with both modalities, the size of tumours was significantly less than either treatment alone (p less than 0.05). These results provide a strong rationale for combining hyperthermia with targeted chemotherapy using microspheres.

Evaluation of ion-exchange microspheres as carriers for the anticancer drug doxorubicin: in-vitro studies.

A comparison study of doxorubicin loading, release characteristics and stability within sodium and hydrogen forms of ion-exchange resin microspheres has been performed. It was demonstrated that resins in the Na+ form, although having lower drug loading capacity, showed similar release profiles to resins in the H+ form but still maintain all the drug activity. Resins in the H+ form, despite having high drug loading capacity, caused drug degradation within microspheres due to their strong acidic nature. Therefore, in comparison with the H+ form, resins in the Na+ form can be considered as better carriers for doxorubicin in terms of sustaining the release of drug and maintaining drug activity. Other factors such as the degree of resin cross-linkage and drug/resin mixing time have also been examined in relation to drug loading and release characteristics. Overall, this study demonstrated the significance of the characteristics of matrix materials and their influence on the drug activity and microsphere performance in-vitro.

Dose response and toxicity of doxorubicin microspheres in a rat tumor model.

The therapeutic response and toxic effects of chemotherapy using several doses of doxorubicin in conventional solution form or bound to an ion-exchange resin were compared in a rat tumor model, to assess the relationship of drug dose to therapeutic efficacy and associated toxicity. Single bolus injections of 3.0, 4.5, 6.0, 7.5 and 9.0 mg/kg were administered via the abdominal aorta to rats bearing hindlimb tumors. Tumor size was measured serially and the growth rates of treated groups were compared with a control growth curve. In addition, the effect of empty microspheres on tumor growth rate was assessed. The levels of circulating white blood cells were measured and compared to control levels to provide an indication of the severity of bone marrow toxicity experienced by each form of treatment. Finally, any difference in the distribution of doxorubicin to tumor, hindlimb and cardiac tissue following administration of doxorubicin as free drug or on microspheres was ascertained. Empty ion-exchange resin exerted a small although significant detrimental effect on tumor growth which may be explained by the embolization of microspheres in the precapillary blood vessels of the tumor resulting in a transient delay in tumor growth rate. The lowest dose of doxorubicin produced a significantly better therapeutic response when administered in the free drug form, but higher doses elicited an equivalent delay in tumor growth for both drug microsphere and free drug groups in a dose-dependent manner, with the maximum anti-tumor response occurring at the highest dose. Treatment with free doxorubicin at high doses resulted in significant reductions of circulating white blood cells suggesting the occurrence of bone marrow toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of schedule on the therapeutic efficacy of chemoimmunotherapy with doxorubicin and interleukin-2.

Combinations of chemotherapeutic agents with recombinant interleukin-2 are currently under investigation in Phase I/II clinical trials as a possible means of improving response rates for metastatic melanoma, breast cancer, non small cell lung and head/neck carcinomas. As chemotherapy often induces marked immune suppression in vivo, the way in which these agents are combined may be of critical consideration to the therapeutic outcome. Using a rat tumour model, this study aimed to define an optimal schedule for the combined administration of doxorubicin (DOX) with interleukin-2 (IL-2). DOX (4.5 mg/kg bolus i.v.) was administered 24 hours before, during, or 24 hours after, IL-2 immunotherapy (1 x 10(5) Cetus U/rat/day for 5 days continuous i.v. infusion) to WAG rats bearing hind limb solid colonic adenocarcinoma implants. Tumour measurements taken over the 4 weeks study period revealed that there was no significant difference in tumour growth inhibition between the three schedules. Furthermore, DOX invariably caused a marked suppression in the rebound lymphoproliferation after cessation of IL-2 therapy (P less than 0.001). These results demonstrate that the therapeutic efficacy of the DOX/IL-2 combination is not influenced by the schedule for the administration of these agents within the times of administration investigated in this study.

Lack of synergy between 5-fluorouracil and interferon-gamma in the treatment of malignancy in the rat.

Numerous in vivo studies have reported synergism between 5-fluorouracil (5-FU) and interferon-gamma (IFN-gamma) but this has not been the case in clinical trials. As the immunomodulatory effects of IFN may be of greater importance in vivo than its direct anti-proliferative activities, it was of interest to determine whether the myelosuppressive effects of high dose 5-FU were responsible for the lack of enhanced activity of the combined drug treatment in the clinical setting. Using an animal model, the anti-tumour activity of three doses of 5-FU (5, 10 and 20 mg/kg/day, continuous intravenous infusion of 7 days) and concurrent IFN-gamma (5 x 10(5) U/kg/day, bolus IV for 5 days) were compared to 5-FU alone. IFN-gamma treatment alone produced a significant anti-tumour response relative to control. No synergism was observed at any dose of 5-FU when combined with IFN-gamma treatment despite white blood cell counts being similar to that in the IFN-gamma group at the lowest dose of 5-FU treatment. Thus, a lack of synergism in vivo is unlikely to be due to myelosuppression resulting in diminished immune response. However, other factors such as tumour type, size and location may be important in determining the final outcome.

Changes in hepatic blood flow during regional hyperthermia.

The influence of liver hyperthermia on hepatic arterial and portal venous blood flow to tumour and normal hepatic tissue was examined in a rabbit VX2 tumour model. Hyperthermia was delivered by 2450 MHz microwave generator to exteriorized livers in 18 rabbits. Blood flow was measured in both portal vein and hepatic artery using radioactive tracer microspheres before, during and 5 min after intense (greater than 43 degrees C) hyperthermia. During hyperthermia a decrease in total liver blood flow was composed primarily of a decrease in hepatic arterial blood flow to tumour tissue. Tumours were supplied almost exclusively by the hepatic artery and thus total tumour blood flow was significantly depressed during heating. The decreased tumour blood flow persisted after the cessation of hyperthermia and was indicative of vascular collapse in the tumour tissue. Temperature differentials in tumour compared to normal tissue ranged from 5 degrees C to 8 degrees C during hyperthermia because of the lower tumour blood flow. The portal vein exerted minimal influence on temperatures attained in the tumour tissue during hyperthermia but would have mediated normal liver tissue heat loss.

Reduced toxicity of adriamycin by incorporation into ion exchange microspheres: a therapeutic study using a rat liver tumour model.

A comparison of the systemic toxicity and therapeutic efficacy of adriamycin carrying microspheres with conventional chemotherapeutic use of adriamycin was performed using a rat liver tumour model. The drug-microspheres were administered via the gastro-duodenal artery for delivery to the liver, whilst similar quantities of free adriamycin were given by systemic intravenous or regional intra-arterial routes. Significant leukopenia, thrombocytopenia and mortality were observed in the systemically treated free drug group (P less than 0.05) with a similar trend for for myelosuppression occurring in the intra-arterial free drug group. The adriamycin-microsphere group showed no toxic side-effects despite retarding tumour growth by similar amounts to the other drug modalities. This work demonstrates a large potential for the use of adriamycin carrying ion-exchange microspheres in the treatment of human malignancy.

Low-dose systemic doxorubicin in combination with regional hepatic hyperthermia.

The influence of regional liver hyperthermia in conjunction with systemic doxorubicin administration was examined in a rabbit VX2 tumour model. Hyperthermia was delivered by 2450MHz microwave generator to the exteriorised livers of the rabbits to provide a thermal dose equivalent of 43 degrees C for 30 minutes. Animals receiving doxorubicin infusion were treated with a total of 1.2 mg/kg over a 3 day protocol through an ear vein. Rabbits were divided into 4 groups; a no treatment control, hyperthermia alone, doxorubicin alone and hyperthermia immediately preceded by doxorubicin. The tumour mass, 10 days post treatment was significantly (P less than 0.0001) reduced in all treatment groups. However, the mean tumour mass in the combination treatment group was also significantly lower than both treatments alone (P less than 0.001). This increased response was not accompanied by any signs of increased systemic or local toxicity associated with any treatment.

Effect of dietary fish oils on the formation of leukotriene B4 and B5, thromboxane and platelet activating factor by rat leukocytes.

1. This study investigates the effect of dietary eicosapentaenoic acid (EPA), in the form of 'Max EPA' fish oil, on leukotriene B4 (LTB4) production in ionophore-stimulated rat leukocytes. Male Wistar rats (200-250 g) were fed for 3 weeks on a synthetic chow supplemented with either 10% by weight Max EPA oil or a coconut oil/safflower oil mixture. 2. The EPA-rich diet significantly increased the EPA content of leukocyte phospholipids and decreased the arachidonic acid level by 35% (P less than 0.001) compared with the control diet. 3. The concentration of leukotrienes in the ionophore (A23187) stimulated leukocytes was measured by reverse-phase HPLC using prostaglandin B2 as the internal standard. The EPA-supplemented diet caused a 50% decrease in LTB4 production (P less than 0.001) and a concomitant increase in the formation of the biologically less active LTB5 compared with the control diet. The amount of LTB4 and LTB5 produced by stimulated leukocytes closely resembled the changes in arachidonic acid and EPA content of leukocyte phospholipids. 4. Thromboxane B2 (TxB2) production in stimulated leukocytes from the EPA-fed animals was also decreased compared with the control group. 5. Although the formation of platelet activating factor by stimulated leukocytes was not altered by dietary treatment, the ability of an EPA-rich diet to decrease LTB4 and TxB2 production suggests that these diets may attenuate leukocyte activity and have useful anti-inflammatory effects.