Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's/Manchester trial

Between 1976 and 1985, 391 patients (202 premenopausal, 189 postmenopausal) with operable breast cancer and positive axillary lymph nodes were randomized after total mastectomy and axillary clearance to receive cyclophosphamide, methotrexate, and fluorouracil (CMF) (n = 193) or no adjuvant therapy (n = 198). After a median follow-up of 8 years, both relapse-free survival (RFS) and survival (S) were significantly prolonged in premenopausal patients receiving CMF (RFS, P less than .001; S, P = .003). Treatment with CMF resulted in a significant improvement in RFS in premenopausal patients both with steroid receptor-positive and steroid receptor-negative tumors and also in subgroups of premenopausal patients defined by the number of axillary nodes involved. Premenopausal patients who developed permanent amenorrhea following CMF had a significantly better RFS than those who continued to menstruate. Induction of amenorrhea following CMF was related to age, with almost all patients over 40 years becoming amenorrheic. For patients less than or equal to 40 years, development of amenorrhea following CMF did not influence outcome. No difference was detected between control and CMF groups (RFS, P = .9; S, P = .9) in postmenopausal patients nor in any subgroup of these patients. The results of this trial of the efficacy of CMF for improving RFS and S have strengthened with longer follow-up.     

Hydrocephalus in posterior fossa tumors in children. Are there factors that determine a need for permanent cerebrospinal fluid diversion?

Objective  We searched for factors that could predispose towards persistent hydrocephalus in children with posterior fossa (PF) tumors in order to determine the need for permanent cerebrospinal fluid (CSF) diversion. Methods  The clinical records of 64 children who underwent surgery for PF tumors in the Pediatric Neurosurgery division of the Hospital of Clinics, Ribeirao Preto, Brazil, from 1990 to 2006, were retrospectively reviewed. The patients’ ages ranged from 3 months to 18 years. The factors evaluated included age at surgery, severity of hydrocephalus (ventricular index), tumor location, size of the tumor, extent of tumor resection, and histology. Results  Ventricular index, measured from the initial neuroradiological image, age at surgery, and location of the tumor were significantly associated with definitive postoperative CSF diversion (shunt or endoscopic third ventriculostomy), which was necessary for 34% of the patients. Conclusions  Young children with severe preoperative hydrocephalus and a midline tumor should be considered at risk when preoperative treatment decisions are made.     

Do patients with advanced breast cancer benefit from chemotherapy?

This study aimed to assess the proportion of patients with advanced breast cancer who report benefit from first-line palliative chemotherapy using a simple global measure of wellbeing and to identify factors predicting benefit. A consecutive series of women with advanced breast cancer undergoing first-line palliative chemotherapy was evaluated. The main outcome measure was patient report of overall wellbeing assessed at post-treatment interview. Physical, psychological and functional status were assessed using the Rotterdam Symptom Checklist (RSCL) on three occasions (pretreatment, at the start of the third cycle and post treatment). It was planned that treatment would be discontinued after six cycles (i.e. 18-24 weeks). One hundred and sixty patients started treatment, of whom 155 were assessable for quality of life. After treatment, 41 (26%) patients reported they felt better, 29 (19%) felt the same and 34 (22%) felt worse than they did before treatment. The other 51 (33%) patients either died or stopped attending the hospital before the post-treatment interview and were assigned as treatment ''failures''. Patients who reported feeling better after treatment had improvements in psychological distress (P < 0.0001), pain (P = 0.01), lack of energy (P = 0.02) and tiredness (P = 0.02), as well as improvement in functional status (P = 0.07). Feeling better was also correlated with disease response (P = 0.03). Feeling worse after treatment or treatment ''failure'' was predicted by the pretreatment presence of a dry mouth (P = 0.003) and high levels of psychological distress (P = 0.03). Pretreatment lack of energy (P = 0.01), dry mouth (P = 0.02), presence of liver metastases (P = 0.03) and breathlessness (P = 0.03) predicted treatment ''failures''. The results of this study suggest that first-line palliative chemotherapy for advanced breast cancer confers benefit on a substantial proportion of patients, with about one-quarter feeling better after treatment and nearly a half feeling better or the same some 4-6 months after the start of treatment. Factors identified in this study may assist clinicians in deciding which patients should not be offered treatment, because of high risk of feeling worse or treatment ''failure''. This work now needs to be validated on a further cohort of women receiving chemotherapy for advanced breast cancer.     

Comparison of 64-slice cardiac computed tomography with myocardial perfusion scintigraphy for assessment of global and regional myocardial function and infarction in patients with low to intermediate likelihood of coronary artery disease

Background. Cardiac computed tomography (CCT) has the potential to assess both coronary anatomy and ventricular function in a single study. We examined the agreement between CCT and myocardial perfusion scintigraphy (MPS) for the assessment of global and regional ventricular function. Methods and Results. Research CCT was performed in 52 patients with a low to intermediate likelihood of coronary artery disease referred for MPS. Left ventricular enddiastolic volume, left ventricular end-systolic volume, left ventricular ejection fraction (LVEF), and myocardial wall motion and thickening were compared between techniques. In addition, myocardial contrast attenuation on CCT was compared with radiotracer uptake on MPS. LVEF values agreed well (mean difference, 4.1%; SD, 15.13%), but CCT left ventricular end-diastolic volume was greater compared with MPS (mean difference, 46.0 mL; SD, 33.34 mL) (P<.001). There was moderate agreement for segmental myocardial motion and thickening, with κ values of 0.57 (95% confidence interval, 0.51–0.63) and 0.47 (95% confidence interval, 0.41–0.53), respectively. Seventeen patients had hypoattenuation in at least 1 myocardial segment on CCT. Three of four patients with concomitant abnormalities of wall motion and thickening on CCT had infarction in the same territory on MPS. Conclusions. There was good agreement for LVEF between CCT and MPS but myocardial volumes differed, and these modalities cannot be used interchangeably. Mild abnormalities of regional function are detected more commonly by CCT than by MPS. Myocardial hypoattenuation on CCT is highly specific for myocardial infarction when associated with reduction of systolic wall thickening and regional wall motion abnormality. Dr Nicol received a grant from the Defence Postgraduate Medical Deanery.     

DNA index, S-phase fraction, histological grade and prognosis in breast cancer

DNA index and S-phase fraction (SPF) were measured by flow cytometry on paraffin embedded tissue from 140 primary breast tumours. The results of DNA analysis were compared with the size, degree of axillary node involvement, histological grade and steroid receptor content of the tumours, as well as with the patients' subsequent clinical course. Forty-four (31.4%) of the 140 tumours were diploid. S-phase fraction was evaluable for 134 (95.7%). The median SPF of the whole population was 7.1%, with diploid tumours having a significantly lower median SPF (3.2%) than aneuploid (10.1%, P less than 0.001). Both aneuploidy (P = 0.002) and high SPF (P less than 0.001) were strongly associated with high histological grade. There was no significant association between either DNA ploidy or SPF and tumour size, nodal status or steroid receptor content. An SPF below the median was strongly associated with better relapse-free survival (P = 0.008), overall survival (P = 0.004) and survival after relapse (P less than 0.001). Ploidy did not correlate significantly with clinical course. Multivariate analysis using the Cox model suggested that, while SPF gave prognostic information independent of tumour size or nodal status, this independent significance was lost when histological grade was included in the analysis.     

Three-dimensional registration of prostate images from histology and ultrasound

A whole mount histology protocol for 3-D tissue reconstruction to compare the size and spatial location of tumors (and other components) identified in histology data with that from 3-D ultrasound (US) images is presented. Prostate specimens are imaged in 3-D using B-mode (US) and sonoelastography. The prostate surface is outlined in each B-mode image and a 3-D surface reconstruction is made. The specimen is then prepared for whole mount histology and the histology slides are digitally reconstructed to make a 3-D surface. These two surfaces are then aligned using a 3-D correlation algorithm, and the tumor boundary determined by the pathologist is compared with that using sonoelastography. 3-D images showing the overlapping histology and sonoelastography of prostate surface reconstructions for one prostate are presented to illustrate the technique; results for four prostates yielded an accuracy of 92% +/- 3%.     

Immunomodulation and protection induced by DNA-hsp65 vaccination in an animal model of arthritis

We described a prophylactic and therapeutic effect of a DNA vaccine encoding the Mycobacterium leprae 65-kDa heat shock protein (DNA-hsp65) in experimental murine tuberculosis. However, high homology of the vaccine to the corresponding mammalian hsp60, together with the CpG motifs in the plasmidial vector, could trigger or exacerbate an autoimmune disease. In the present study, we evaluate the potential of DNA-hsp65 vaccination to induce or modulate arthritis in mice genetically selected for acute inflammatory reaction (AIR), either maximal (AIRmax) or minimal (AIRmin). Mice immunized with DNA-hsp65 or injected with the corresponding DNA vector (DNAv) developed no arthritis, whereas pristane injection resulted in arthritis in 62% of AIRmax mice and 7.3% of AIRmin mice. Administered after pristane, DNA-hsp65 downregulated arthritis induction in AIRmax animals. Levels of interleukin (IL)-12 were significantly lower in mice receiving pristane plus DNA-hsp65 or DNAv than in mice receiving pristane alone. However, when mice previously injected with pristane were inoculated with DNA-hsp65 or DNAv, the protective effect was significantly correlated with lower IL-6 and IL-12 levels and higher IL-10 levels. Our results strongly suggest that DNA-hsp65 has no arthritogenic potential and is actually protective against experimentally induced arthritis in mice.