Gene-engineered T cells as a superior adjuvant therapy for metastatic cancer

The major limiting factor in the successful application of adjuvant therapy for metastatic disease is the lack of adjuvant specificity that leads to severe side effects. Reasoning that T cells of the immune system are highly specific, we generated tumor-specific T cells by genetic modification of mouse primary T cells with a chimeric receptor reactive with the human breast cancer-associated Ag erbB-2. These T cells killed breast cancer cells and secreted IFN-gamma in an Ag-specific manner in vitro. We investigated their use against metastatic breast cancer in mice in an adjuvant setting, and compared their effectiveness with the commonly applied adjuvants doxorubicin, 5-fluorouracil, and herceptin. Mice were inoculated orthotopically with the human erbB-2-expressing spontaneously metastatic mouse breast cancer 4T1.2 in mammary tissue, and the primary tumor was surgically removed 8 days later., Significant metastatic disease was demonstrated in lung and liver at the time of surgery on day 8 with increased tumor burden at later time points. T cell adjuvant treatment of day 8 metastatic disease resulted in dramatic increases in survival of mice, and this survival was significantly greater than that afforded by either doxorubicin, 5-fluorouracil, or herceptin.

Positive end expiratory pressure during resuscitation of premature lambs rapidly improves blood gases without adversely affecting arterial pressure

Positive end expiratory pressure (PEEP) is important for neonatal ventilation but is not considered in guidelines for resuscitation. Our aim was to investigate the effects of PEEP on cardiorespiratory parameters during resuscitation of very premature lambs delivered by hysterotomy at similar to125 d gestation (term similar to147 d). Before delivery, they were intubated and lung fluid was drained. Immediately after delivery, they were ventilated with a Drager Babylog plus ventilator in volume guarantee mode with a tidal volume of 5 mL/kg. Lambs were randomized to receive 0, 4, 8, or 12 cm H2O of PEEP. They were ventilated for a 15-min resuscitation period followed by 2 h of stabilization at the same PEEP. Tidal volume, peak inspiratory pressure, PEEP, arterial pressure, oxygen saturation, and blood gases were measured regularly, and respiratory system compliance and alveolar/ arterial oxygen differences were calculated. Lambs that received 12 cm H2O of PEEP died from pneumothoraces; all others survived without pneumothoraces. Oxygenation was significantly improved by 8 and 12 cm H2O of PEEP compared with 0 and 4 cm H2O of PEEP. Lambs with 0 PEEP did not oxygenate adequately. The compliance of the respiratory system was significantly higher at 4 and 8 cm H2O of PEEP than at 0 PEEP. There were no significant differences in partial pressure of carbon dioxide in arterial blood between groups. Arterial pressure was highest with 8 cm H2O of PEEP, and there was no cardiorespiratory compromise at any level of PEEP. Applying PEEP during resuscitation of very premature infants might be advantageous and merits further investigation.

Breast cancer in Western Australia: clinical practice and clinical guidelines

Objectives: To review changes in patterns of care for women with early invasive breast cancer in Western Australia from 1989 to 1999, and compare management with recommendations in the 1995 National Health and Medical Research Council guidelines. Design and setting: Population-based surveys of all cases listed in the Western Australian Cancer Registry and Western Australian Hospital Morbidity Data System. Main outcome measures: Congruence of care with guidelines. Results: Data were available for 1649 women with early invasive breast cancer (categories pT1 or pT2; pN0 or pN1; and M0). In 1999, 96% had a preoperative diagnosis by fine-needle aspiration or core biopsy (compared with 66% in 1989), with a synoptic pathology report on 95%. Breast-conserving surgery was used for 66% of women with mammographically detected tumours (v 35% in 1989) and 46% of those with clinically detected tumours (v 28% in 1989), with radiotherapy to the conserved breast in 90% of these cases (83% in 1989). Adjuvant chemotherapy was given to 92% of premenopausal women with node-positive disease and 63% with poor-prognosis node-negative tumours (v 78% and 14%, respectively, in 1989). Among postmenopausal women with receptor-positive tumours, tamoxifen was prescribed for 91% of those with positive nodes (85% in 1989) and 79% of those with negative nodes (30% in 1989). Among postmenopausal women with receptor-negative tumours, chemotherapy was prescribed for 70% with positive nodes (v 33%) and 58% with negative nodes (v none). Conclusions: Patterns of management of women with early invasive breast cancer in Western Australia during the 1990s changed significantly in all respects toward those recommended in the 1995 guidelines.

Evaluating curriculum changes in undergraduate cancer education

Background. Previous studies have indicated that Australian medical schools have not adequately prepared our graduating doctors to care for patients with cancer. The University of Western Australia (UWA) introduced a two-week clinical attachment in cancer medicine for fifth-year students in 2000 and a four-day clinical attachment in palliative care for sixth-year students in 2001. This article evaluates the introduction of these dedicated clinical attachments in cancer and palliative care. Method. The Australian Cancer Society's Cancer Education Survey was administered to the UWA graduates starting their intern year in teaching hospitals in Perth, Western Australia, in 2002. Their responses were compared with data collected in a similar national survey of Australian and New Zealand interns in 2001. Results. The response rate was 56% (n = 70). When compared with the national data for 2001, more UWA interns (2002) would refer a newly diagnosed breast cancer patient to a multidisciplinary breast clinic (97% vs. 74%, P<.001). Fewer UWA 2002 interns rated their training as poor or very poor in the management of patients with incurable cancer (19% vs. 35%, P=.008) and the management of symptoms in patients dying from cancer (10% vs. 37%, P<.001), but they were more likely to rate their training in assisting a patient to stop smoking as poor or very poor (54% vs. 21%, P<.001). Only a quarter of the UWA 2002 interns had examined a patient with a cancer of the mouth or tongue (25% vs. 49%, P<.001), and only two thirds had examined a patient with lymphoma (64% vs. 83%, P<.001). Conclusions. Our data reflect changes in the final two years of the medical course at UWA and suggest that the introduction of dedicated attachments in cancer and palliative care has better prepared graduating doctors to care for patients with cancer.

Evaluation of the Binding Properties of Maghemite Nanoparticle Surface-Coated with Meso-2-3-Dimercaptosuccinic Acid to Serum Albumin

In this study the interaction between magnetic nanoparticles (MNPs) surface-coated with meso-2,3-dimercaptosuccinic acid (DMSA) with both bovine serum albumin (BSA) and human serum albumin (HSA) was investigated. The binding of the MNP-DMSA was probed by the fluorescence quenching of the BSA and HSA tryptophan residue. Magnetic resonance and light microscopy analyses were carried out in in vivo tests using female Swiss mice. The binding constants (K(b)) and the complex stoichiometries (n) indicate that MNP-DMSA/BSA and MNP-DMSA/HSA complexes have low association profiles. After five minutes following intravenous injection of MNP-DMSA into mice`s blood stream we found the lung firstly target by the MNP-DMSA, followed by the liver in a latter stage. This finding suggests that the nanoparticle`s DMSA-coating process probably hides the thiol group, through which albumin usually binds. This indicates that biocompatible MNP-DMSA is a very promising material system to be used as a drug delivery system (DDS), primarily for lung cancer treatment.

Surgical management of lung cancer in Western Australia in 1996 and its outcomes

Background: All cases of lung cancer diagnosed in Western Australia in 1996 in which surgery was the primary treatment, were reviewed. Reported herein are the characteristics of the patients, the treatment outcomes and a comparison of the management undertaken with that recommended by international guidelines. Methods: All patients with a new diagnosis of lung cancer in Western Australia in the calendar year of 1996 were identified using two different population-based registration systems: the Western Australian (WA) Cancer Registry and the WA Hospital Morbidity Data System. A structured questionnaire on the diagnosis and management was completed for each case. Date of death was determined through the WA Cancer Registry. Results: Six hundred and sixty-eight patients with lung cancer were identified; 132 (20%) were treated with surgery. Lobectomy was the most frequently performed procedure (71%), followed by pneumonectomy (19%). Major complications affected 23% of patients. Postoperative mortality was 6% (3% lobectomy, 12% pneumonectomy). At 5 years the absolute survival was as follows for stage I, II, IIIA, IIIB, respectively: 51%, 45%, 12%, 5%. Conclusions: Investigations and choice of surgery in WA in 1996 reflect current international guidelines. The survival of patients with resectable lung cancer remains unsatisfactory.

Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke - a randomized substudy

Background and Purpose - Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine ( total homocysteine [tHcy]) accelerate cardiovascular disease by promoting vascular inflammation, endothelial dysfunction, and hypercoagulability. Methods - We conducted a randomized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg, vitamin B-12 0.5 mg, and vitamin B-6 25 mg compared with placebo on laboratory markers of vascular inflammation, endothelial dysfunction, and hypercoagulability. Results - At 6 months after randomization, there was no significant difference in blood concentrations of markers of vascular inflammation (high-sensitivity C-reactive protein [P = 0.32]; soluble CD40L [ P = 0.33]; IL-6 [P = 0.77]), endothelial dysfunction ( vascular cell adhesion molecule-1 [P = 0.27]; intercellular adhesion molecule-1 [P = 0.08]; von Willebrand factor [P = 0.92]), and hypercoagulability (P-selectin [P = 0.33]; prothrombin fragment 1 and 2 [P = 0.81]; D-dimer [P = 0.88]) among patients assigned vitamin therapy compared with placebo despite a 3.7-mumol/L (95% CI, 2.7 to 4.7) reduction in total homocysteine (tHcy). Conclusions - Lowering tHcy by 3.7 mumol/L with folic acid-based multivitamin therapy does not significantly reduce blood concentrations of the biomarkers of inflammation, endothelial dysfunction, or hypercoagulability measured in our study. The possible explanations for our findings are: ( 1) these biomarkers are not sensitive to the effects of lowering tHcy (eg, multiple risk factor interventions may be required); ( 2) elevated tHcy causes cardiovascular disease by mechanisms other than the biomarkers measured; or ( 3) elevated tHcy is a noncausal marker of increased vascular risk.

Surgical caseload and outcomes for women with invasive breast cancer treated in Western Australia

We have assessed the outcomes for all women diagnosed with invasive breast cancer in Western Australia during 1989, 1994 and 1999, and compared the results for surgeons who treat 20 or more cases per year with those of surgeons who treat less. Women treated by high caseload surgeons were more likely to retain their breast (53.3% vs. 36.7%, p < 0.001), have adjuvant radiotherapy (50.0% vs. 30.6%, p < 0.001), and be alive after 4 years (1989, 86% vs. 82%; 1994, 89% vs. 84%; 1999, 90% vs. 79%, HR 0.71, p = 0.03). Adjusting for age and year of diagnosis, women were not more likely to be treated with adjuvant chemotherapy (29.2% vs. 20.9%, p = 0.28). In 1989 35% of women were treated by high caseload surgeons. By 1999 this had risen to 82%. The results confirm that women treated by high caseload surgeons have better outcomes. (C) 2004 Elsevier Ltd. All rights reserved.