Chemotherapy-induced alopecia (CIA) represents perhaps the most distressing side effect of chemotherapeutic agents and is of huge concern to the majority of patients. Scalp cooling is currently the only safe option to combat CIA. Clinical and biological evidence suggests improvements can be made, including efficacy in delivering adequately low temperature to the scalp and patient-specific cap design. The increased use of scalp cooling, an understanding of how to deliver it most effectively, and biological evidence-based approaches to improve its efficacy have enormous potential to ease the psychological burden of CIA, as this could lead to improvements in treatment and patient quality-of-life.

Background:The lipogenic transcription factor carbohydrate response element-binding protein (ChREBP) may play a key role in malignant progression of breast cancer by allowing metabolic adaptations to take place in response to changes in oxygenation.Methods:Immunohistochemical analysis of ChREBP was carried out in human breast tumour tissue microarrays representative of malignant progression from normal breast through to metastatic cancer. The ChREBP protein and mRNA expressions were then analysed in a series of breast cancers for correlative analysis with common and breast-specific hypoxia signatures, and survival.Results:In invasive ductal carcinoma, ChREBP correlated significantly with mean ‘downregulated' hypoxia scores (r=0.3, P<0.015, n=67) and in two distinct breast progression arrays, ChREBP protein also increased with malignant progression (P<0.001). However, bioinformatic analysis of a large data set (2136 cases) revealed an apparent reversal in the relationship between ChREBP mRNA level and clinical outcome – not only being significantly correlated with increased survival (log rank P<0.001), but also downregulated in malignant tissue compared with adjacent normal tissue.Conclusion:The ChREBP expression may be reflective of an aerobic metabolic phenotype that may conflict with hypoxia-induced signalling but provide a mechanism for growth at the oxygenated edge of the tumours.

A highly distressing side-effect of cancer chemotherapy is chemotherapy-induced alopecia (CIA). Scalp cooling remains the only treatment for CIA, yet there is no experimental evidence to support the cytoprotective capacity of cooling. We have established a series of in vitro models for the culture of human keratinocytes under conditions where they adopt a basal, highly-proliferative phenotype thus resembling the rapidly-dividing sub-population of native hair-matrix keratinocytes. Using a panel of chemotherapy drugs routinely used clinically (docetaxel, doxorubicin and the active metabolite of cyclophosphamide 4-OH-CP), we demonstrate that although these drugs are highlycytotoxic, cooling can markedly reduce or completely inhibit drug cytotoxicity, in agreement with clinical observations. By contrast, we show that cytotoxicity caused by specific combinatorial drug treatments cannot be adequately attenuated by cooling, supporting data showing that such treatments do not always respond well to cooling clinically. Importantly, we provide evidence that the choice of temperature may be critical in determining the efficacy of cooling in rescuing cells from drug-mediated toxicity. Therefore, despite their reductive nature, these in vitro models have provided experimental evidence for the clinically-reported cytoprotective role of cooling and represent useful tools for future studies on the molecular mechanisms of cooling-mediated cytoprotection. Chemotherapy-induced alopecia (CIA) is the most common and distressing side effect of anticancer chemotherapy (Wang et al., 2006) and the anxiety caused by the prospect of CIA can cause patients to even refuse treatment in certain cases (Munstedt et al., 1997). Thus development of an effective CIA preventative regime represents an important challenge in oncology (Paus et al., 2013). CIA occurs due to damage to the hair follicles, which comprise various cell types including hair matrix keratinocytes, which represent the most rapidly dividing cell subset and contribute to follicular structure and function (Roh et al., 2005). As chemotherapeutic drugs such as taxanes (e.g. docetaxel), alkylating agents (e.g. cyclophosphamide) and anthracyclines/DNA intercalating agents (e.g. doxorubicin) target cancer cells due to their rapid division rate, these drugs also target the matrix keratinocytes which results in hair loss (Paus et al., 2013). AbbreviationsCurrently the only available preventative treatment for CIA is head (scalp) cooling. Scalp cooling or hypothermia during the administration of chemotherapy drugs can substantially reduce hair loss (Protiere et al., 2002) and has been used since the 1970s (Dean et al., 1979). Clinically it has been shown that scalp cooling can substantially reduce the incidence of hair loss in response to individual drugs, including cyclophosphamide, doxorubicin and cisplatin (Breed et al., 2011;van den Hurk et al., 2012). However, for combined treatment regimens, such as sequential treatment with docetaxel (taxotere), doxorubicin (adriamycin) an...

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