Changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer.

INTRODUCTION: Although neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of aldehyde dehydrogenase-1 (ALDH1) is associated with the stem-like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumor samples treated with NAC could identify women more likely to benefit from this therapy. METHODS: Women with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumor specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumor response using Fisher's exact test while Kaplan-Meier method was used to calculate survival. RESULTS: A hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumor grade, stage, hormone receptor, human epidermal growth factor receptor 2 (HER2) status and Ki67 index. ALDH1 negativity at baseline was significantly associated with pCR (P = 0.004). The presence of ALDH1(+) cells in the residual tumor cells in non-responding women was strongly predictive of worse overall survival (P = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumor-specific ALDH1 expression (P = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel chemotherapy showed an unexpected significant increase in ALDH1 expression. CONCLUSIONS: ALDH1 expression is a useful predictor of chemoresistance. The up-regulation of ALDH1 after NAC predicts poor survival in locally advanced breast cancer. Although the chemotherapy sequence had no effect on overall prognosis, our results suggest that anthracycline-based chemotherapy may be more effective at targeting ALDH1(+) breast cancer cells. TRIAL REGISTRATION: ACTRN12605000588695.

Comparison of computed radiography and multi-detector computed tomography in the detection of post mortem metacarpal index.

BACKGROUND: The sudden, unexpected death of young persons from ruptured thoracic aortic dissection is suggestive of Marfan syndrome (MFS), a genetic disorder of fibrillin. Establishing such a diagnosis is important so that the same fate might be avoided in living relatives. MFS diagnosis is difficult in the deceased but the presence of arachnodactyly, a common morphological feature of MFS, can be established by assessing the metacarpal index (MCI). MCI is routinely determined using radiographic techniques including computed radiography (CR). The wider availability of computed tomography (CT) in the forensic environment provides an alternative method. CT is predicted to produce measurements at least as accurate as CR. The aims of this study therefore were to (1) validate MCI measurements by comparing CT and CR with direct measurement using calipers on human skeletonised hands, and (2) compare cadaveric CT and CR MCI measurements. METHODS: The metacarpals of 12 human skeleton hands were measured using CT and CR, and compared with direct measurement using calipers (the "gold standard"). Fifty randomly selected cadavers between 20 and 40 years had the MCI of both hands measured using CT and CR. RESULTS: CT was found to be more accurate in the measurement of MCI than CR. There were significant differences in the MCIs obtained for CT and CR (females: p=0.01; males: p<0.0001) and between CR and calipers (p=0.004). There were no significant differences between MCIs obtained for CT and calipers (p=0.71). CR was found to consistently overestimate the MCI by an average of 7.97%. CONCLUSION: CT is more accurate in determination of the MCI than CR and should provide the basis for future skeletal measurements.