Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial.

BACKGROUND: The optimal sequence of adjuvant chemotherapy and radiotherapy for breast cancer is unknown. SECRAB assesses whether local control can be improved without increased toxicity. METHODS: SECRAB was a prospective, open-label, multi-centre, phase III trial comparing synchronous to sequential chemo-radiotherapy, conducted in 48 UK centres. Patients with invasive, early stage breast cancer were eligible. Randomisation (performed using random permuted block assignment) was stratified by centre, axillary surgery, chemotherapy, and radiotherapy boost. Permitted chemotherapy regimens included CMF and anthracycline-CMF. Synchronous radiotherapy was administered between cycles two and three for CMF or five and six for anthracycline-CMF. Sequential radiotherapy was delivered on chemotherapy completion. Radiotherapy schedules included 40 Gy/15F over three weeks, and 50 Gy/25F over five weeks. The primary outcome was local recurrence at five and ten years, defined as time to local recurrence, and analysed by intention to treat. ClinicalTrials.gov NCT00003893. FINDINGS: Between 02-July-1998 and 25-March-2004, 2297 patients were recruited (1150 synchronous and 1146 sequential). Baseline characteristics were balanced. With 10.2 years median follow-up, the ten-year local recurrence rates were 4.6% and 7.1% in the synchronous and sequential arms respectively (hazard ratio (HR) 0.62; 95% confidence interval (CI): 0.43-0.90; p = 0.012). In a planned sub-group analysis of anthracycline-CMF, the ten-year local recurrence rates difference were 3.5% versus 6.7% respectively (HR 0.48 95% CI: 0.26-0.88; p = 0.018). There was no significant difference in overall or disease-free survival. 24% of patients on the synchronous arm suffered moderate/severe acute skin reactions compared to 15% on the sequential arm (p < 0.0001). There were no significant differences in late adverse effects apart from telangiectasia (p = 0.03). INTERPRETATION: Synchronous chemo-radiotherapy significantly improved local recurrence rates. This was delivered with an acceptable increase in acute toxicity. The greatest benefit of synchronous chemo-radiation was in patients treated with anthracycline-CMF. FUNDING: Cancer Research UK (CR UK/98/001) and Pharmacia.

Lesson of the month 2: Oncology, obstetrics and orthopaedics: an unusual partnership.

Breast cancer diagnosed during pregnancy is a relatively uncommon event. This challenging situation presents clinicians with difficult decisions, often requiring a multidisciplinary approach at a time of heightened anxiety for the patient and their family. This paper describes the case of a young woman with metastatic breast cancer diagnosed in early pregnancy, and outlines how this complex clinical situation was managed.

Differential roles of extracellular signal-regulated kinase 1/2 and p38MAPK in mechanical load-induced procollagen alpha1(I) gene expression in cardiac fibroblasts.

OBJECTIVE AND METHODS: We have previously demonstrated that mechanical loading of cardiac fibroblasts leads to increased synthesis and gene expression of the extracellular matrix protein collagen. We hypothesised that the upregulation of procollagen gene expression in cardiac fibroblasts, in response to cyclic mechanical load, is mediated by one or more members of the MAP kinase family. To test this hypothesis, the effect of mechanical load on the activation of extracellular signal-regulated kinase (ERK) 1/2, p46/54JNK, and p38MAPK was examined in rat cardiac fibroblasts. RESULTS: Peak phosphorylation of ERK 1/2, p38MAPK kinases, and p46/54JNK was observed following 10-20 min of continuous cyclic mechanical load. Mechanical load significantly increased procollagen alpha1(I) mRNA levels up to twofold above static controls after 24 h. This increase was completely abolished by the MEK 1/2 inhibitor U0126, with no effect on basal levels. In contrast, SB203580, a specific inhibitor of p38MAPK, enhanced both basal and stretch-stimulated levels of procollagen mRNA. Consistent with this finding, selective activation of the p38MAPK signalling pathway by expression of MKK6(Glu), a constitutive activator of p38MAPK, significantly reduced procollagen alpha1(I) promoter activity. SB203580-dependent increase in procollagen alpha1(I) was accompanied by ERK 1/2 activation, and inhibition of this pathway completely prevented SB203580-induced procollagen alpha1(I) expression. CONCLUSIONS: These results suggest that mechanical load-induced procollagen alpha1(I) gene expression requires ERK 1/2 activation and that the p38MAPK pathway negatively regulates gene expression in cardiac fibroblasts. These pathways are likely to be key in events leading to matrix deposition during heart growth and remodelling induced by mechanical load.

Intractable malignant ascites: an alternative management option.

BACKGROUND: Recurrent malignant ascites is a common management problem in oncology and palliative care. DISCUSSION: Here, we describe a case of malignant ascites managed by insertion of a Tenckhoff Catheter (TC), which resulted in successful symptomatic control and improvement in quality of life.

Activation of fibroblast procollagen alpha 1(I) transcription by mechanical strain is transforming growth factor-beta-dependent and involves increased binding of CCAAT-binding factor (CBF/NF-Y) at the proximal promoter.

During normal developmental tissue growth and in a number of diseases of the cardiopulmonary system, adventitial and interstitial fibroblasts are subjected to increased mechanical strain. This leads to fibroblast activation and enhanced collagen synthesis, but the underlying mechanisms involved remain poorly understood. In this study, we have begun to identify and characterize mechanical strain-responsive elements in the rat procollagen alpha 1(I) (COL1A1) gene and show that the activity of COL1A1 promoter constructs, transiently transfected into cardiac fibroblasts, was increased between 2- and 4-fold by continuous cyclic mechanical strain. This was accompanied by an approximately 3-fold increase in the levels of total active transforming growth factor-beta (TGF-beta) released into the medium. Inclusion of a pan-specific TGF-beta neutralizing antibody inhibited strain-induced COL1A1 promoter activation. Deletion analysis revealed the presence of two potential strain response regions within the proximal promoter, one of which contains an inverted CCAAT-box overlapping a GC-rich element. Both mechanical strain and exogenously added TGF-beta1 enhanced the binding activity of CCAAT-binding factor, CBF/NF-Y, at this site. Moreover, this element was sufficient to confer strain-responsiveness to an otherwise unresponsive SV40 promoter. In summary, this study demonstrates that strain-induced COL1A1 promoter activation in cardiac fibroblasts is TGF-beta-dependent and involves increased binding of CCAAT-binding factor at the proximal promoter. Furthermore, these findings suggest a novel and potentially important TGF-beta response element in the rat COL1A1 gene.