MD Francisco Javier Andreu
email: fjandreu@mac.com

Histologic diagnosis in young women with breast cancer

Introduction

Breast cancer is a heterogeneous group of tumors with similar diagnostic, but different prognostic profiles that can be subdivided on the basis of histopathological features, genetic alterations and gene-expression profiles. The World Health Organization has defined a wide range of histopathological subtypes of invasive breast cancer and classified these carcinomas into 19 categories, most of which are quite rare [START_REF] Tavassoli | Pathology and genetics of tumours of the breast and female genital organs[END_REF]. This classification into tumor subtypes is based on histopathological characteristics, and reflects differences in biological behavior and, in general lines, different outcomes.

However, the main criticism to this classification is that >80% of the tumor subtypes are infiltrating ductal carcinomas not otherwise specified (NOS). For this reason, histological grading systems, which do have prognostic value, have been elaborated.

Using an intrinsic set of 534 genes, Sørlie et al. [START_REF] Sorlie | Repeated observation of breast tumor subtypes in independent gene expression data sets[END_REF] analyzed the expression profiles of 115 independent breast tumor samples and categorized breast tumors into five groups: 1) luminal A; 2) luminal B; 3) human epidermal growth factor receptor-2 (HER2) enriched (i.e. tumors that overexpress ErbB2-associated genes but do not express genes that define the luminal subtype); 4) normal breast-like; and 5) basal-like. Each group of tumors has different prognoses and clinical outcomes.

Histological subtypes of breast cancer

Luminal A and luminal B tumors

The traditional division of breast cancers into "endocrine receptor positive or negative" helps guide patient management. Luminal subtype A and B tumors express estrogen receptors (ER), GATA3, and genes regulated by both ER and GATA3 [START_REF] Usary | Mutation of GATA3 in human breast tumors[END_REF][START_REF] Finlin | RERG is a novel ras-related, estrogen-regulated and growth-inhibitory gene in breast cancer[END_REF]. Compared with luminal B tumors, luminal A tumors express higher levels of ER and GATA3 and show more favorable patient outcomes in both the presence and the absence of systemic adjuvant therapy [START_REF] Sorlie | Repeated observation of breast tumor subtypes in independent gene expression data sets[END_REF], whereas luminal B tumors more often express human epidermal growth factor receptor-1 (HER1 or epidermal growth factor receptor [EGFR]), HER2, and/or cyclin E1 [START_REF] Sorlie | Repeated observation of breast tumor subtypes in independent gene expression data sets[END_REF][START_REF] Sorlie | Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications[END_REF]. Although some luminal B tumors can be identified by their expression of HER2 (HER2 positive or HER2+), the major biological distinction between luminal A and B is the proliferation signature, including genes such as CCNB1, MYBL2, and MKI67 (encoding Ki-67), which have a higher expression in luminal B tumors than in luminal A tumors [START_REF] Perou | Distinctive gene expression patterns in human mammary epithelial cells and breast cancers[END_REF].

Breast cancers expressing high levels of Ki-67, a nuclear marker of cell proliferation, are associated with worse outcomes [START_REF] De Azambuja | Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients[END_REF]. As suggested from gene-expression profiling, coexpression of HER2 and ER and/or progesterone receptor (PR) can identify some luminal B tumors (i.e., the luminal -HER2+ group). However, only approximately 30% of luminal B tumors are HER2+, indicating that this clinical marker alone is not sensitive enough to identify most luminal B breast cancers [START_REF] Cheang | Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer[END_REF]. Ki-67 can be added concurrently to the standard biomarker panel of ER, PR, and HER2 to identify additional luminal B tumors that would not be identified by these three markers [START_REF] Cheang | Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer[END_REF].

HER2 enriched tumors

HER2+ tumors fall into at least two distinct expression groups: those which are ERand typically cluster near basal-like tumors (HER2+/ER-subtype), and those which are ER+ (which may also be PR+) and cluster with tumors of luminal cell origins as part of the luminal B subtype [START_REF] Sorlie | Repeated observation of breast tumor subtypes in independent gene expression data sets[END_REF][START_REF] Sorlie | Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications[END_REF].

Basal-like tumors

Basal-like tumors typically show low expression of HER2 and ER and exhibit high expression of genes that characterize the basal epithelial cell layer, including genes responsible for the expression of cytokeratins 5, 6, and 17 [START_REF] Perou | Molecular portraits of human breast tumours[END_REF]. There is some confusion in the literature as to what defines a basal-like tumor. The term was introduced by Perou et al. [START_REF] Perou | Molecular portraits of human breast tumours[END_REF] as describing a subgroup of tumors defined by their great similarity in overall gene-expression pattern of the "intrinsic gene subset" when unsupervised hierarchical clustering was applied. As outlined above, several studies have indicated that these basal-like tumors have low mRNA expression of ER, PR and HER2 genes, and are usually also negative for expression of ER, PR and HER2 measured using immunohistochemistry.

Epidemiological data of breast cancer subtypes

The prevalence among these subtypes of breast cancer in young women varies from one study to another [START_REF] Lin | Molecular subtypes of breast cancer emerging in young women in Taiwan: evidence for more than just westernization as a reason for the disease in Asia[END_REF][START_REF] Ihemelandu | Molecular breast cancer subtypes in premenopausal African-American women, tumor biologic factors and clinical outcome[END_REF]. In a study by Lin et al. [START_REF] Lin | Molecular subtypes of breast cancer emerging in young women in Taiwan: evidence for more than just westernization as a reason for the disease in Asia[END_REF], younger (<50 years) breast cancer patients had a higher prevalence of luminal A (67%) and a lower prevalence of basal-like (9%) subtype. The higher prevalence of luminal A subtype in this study population was mainly attributed to a higher ER and PR expression rate in younger patients than in older patients.

Also in the study by Ihemelandu et al. [START_REF] Ihemelandu | Molecular breast cancer subtypes in premenopausal African-American women, tumor biologic factors and clinical outcome[END_REF], the luminal A subtype was the most prevalent (50%) compared with basal-like (23%), luminal B (14%), and HER2 (13%) subtypes. However, when stratified by age groups, results showed that in women under 35 years the basal-like subtype was the most prevalent (56%), in comparison with 26%, 15%, and 6% for luminal A, luminal B, and HER2 subtypes, respectively.

Other important results from this study regarding women younger than 35 years of age were that P53 mutations were more prevalent in basal-like subtypes compared with luminal A subtypes (48% vs 19%). Luminal B subtypes are more likely to overexpress the Bcl-2 gene than luminal A subtypes. Though not statistically significant, HER-2/neu and basal-cell-like subtypes had the shortest survival time [START_REF] Ihemelandu | Molecular breast cancer subtypes in premenopausal African-American women, tumor biologic factors and clinical outcome[END_REF]. The high prevalence of the basal-like subtype in young premenopausal women aged <35 years may contribute to the poorer prognosis observed in this cohort of women.

The probability of remaining disease-free is significantly different between subtypes; patients with luminal A type tumors live considerably longer before they develop metastatic disease, whereas the basal-like and HER2 subtypes show much shorter disease-free time intervals [START_REF] Sorlie | Repeated observation of breast tumor subtypes in independent gene expression data sets[END_REF]. The basal-like subtype has been associated with poor clinical outcomes [START_REF] Sorlie | Repeated observation of breast tumor subtypes in independent gene expression data sets[END_REF][START_REF] Sotiriou | Breast cancer classification and prognosis based on gene expression profiles from a population-based study[END_REF], which likely reflect this subtype's high proliferative capacity [START_REF] Sorlie | Repeated observation of breast tumor subtypes in independent gene expression data sets[END_REF][START_REF] Sorlie | Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications[END_REF][START_REF] Sotiriou | Breast cancer classification and prognosis based on gene expression profiles from a population-based study[END_REF] as well as the lack of directed therapies, since typically basal-like tumors do not express ER or overexpress HER2 [START_REF] Nielsen | Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma[END_REF].

Histological characterization of basal-like breast cancers

Among the five intrinsic subtypes, basal-like breast cancers have drawn particular attention, because they do not express ER, PR, or HER2 (i.e. triple negative tumors), and therefore are not be expected to benefit from anti-estrogen therapies nor from trastuzumab [START_REF] Slamon | Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2[END_REF].

Approximately 80% to 90% of triple negative breast cancers are deemed to be basallike when appropriately tested for immunohistochemical markers and gene expression.

Moreover, there is a consistent trend across studies confirming unfavorable clinical outcomes associated with the triple negative phenotype and basal-like breast cancer [START_REF] Sorlie | Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications[END_REF][START_REF] Nielsen | Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma[END_REF][START_REF] Bauer | Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)negative, and HER2-negative invasive breast cancer, the so-called triplenegative phenotype: a population-based study from the California cancer Registry[END_REF].

Additional efforts have been made to characterize basal-like tumors with standard histopathology and immunohistochemical analyses [START_REF] Nielsen | Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma[END_REF][START_REF] Kim | Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and Her2/neu-overexpressing phenotypes[END_REF]. Nielsen et al. identified a panel of antibodies (anti ER, EGFR, HER2 and cytokeratin 5/6) that could accurately discriminate basal-like tumors from the other molecular subtypes. They used a panel of 21 basal-like tumors defined by gene-expression profiling, and correlated their immunohistochemical features with those obtained from a series of 663 breast tumors. They found that 15% were of the basal-like subtype and all of them stained negative for ER, PR and HER2 and positive for cytokeratin 5/6 and/or EGFR [START_REF] Nielsen | Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma[END_REF].

In another study, Kim et al. studied 776 breast tumors using immunohistochemistry, which were subdivided into five groups based on the pattern of marker expression.

Basal-like tumors were defined by negative staining for ER, PR and HER2, and positive staining for cytokeratin 5 and/or cytokeratin 14 and/or EGFR and/or cKIT [START_REF] Kim | Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and Her2/neu-overexpressing phenotypes[END_REF]. This subtypes were also associated with TP53 mutations [START_REF] Sorlie | Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications[END_REF].

Recently, in a microarray study of basal cytokeratin expression and related immunohistochemical markers, breast cancers that were positive for cytokeratin 5/6 were found to be associated with expression of EGFR, with the proliferation marker Ki-67, with accumulation of p53 and with increased cytogenetic abnormalities [START_REF] Korsching | Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis[END_REF]. In another recent study, the basal-like subtype, as defined by cytokeratin 5/6 expression by immunohistochemistry, was also found to be common among breast cancer patients with hereditary BRCA1 mutations [START_REF] Foulkes | Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer[END_REF].

BRCA1-associated breast carcinomas usually have a basal-like phenotype [START_REF] Perou | Molecular portraits of human breast tumours[END_REF], are of higher grade (usually grade 3), have a higher mitotic count, are TP53-mutated, are ER and HER2 negative, and are characterized by the expression of basal or myoepithelial markers such as basal keratins, P-cadherin and EGFR [START_REF] Foulkes | Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer[END_REF][START_REF] Honrado | The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications[END_REF][21][START_REF] Grushko | Molecular-cytogenetic analysis of HER-2/neu gene in BRCA1associated breast cancers[END_REF]. On the other hand, BRCA2-associated breast carcinomas are rarely basal-like phenotype, also are of higher grade (usually grade 2/3) than sporadic age-matched controls [21], and tend to be ER and PR positive [START_REF] Robson | A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment[END_REF].

The observation that BRCA1 mutations are strongly associated with a basal tumor phenotype indicates a particularly poor prognosis for patients carrying this mutation.

BRCA1 status in familial cancers has failed to be an independent prognostic factor in several studies [START_REF] Kennedy | BRCA1: mechanisms of inactivation and implications for management of patients[END_REF], and is complicated by confounding factors such as frequent screening and early diagnosis.

Conclusions

Breast cancer can be categorized into five histological groups such as luminal A, luminal B, HER2+, normal breast-like, and basal-like. Prevalence of breast cancer in young women varies from one study to another, but based in its histological characteristics is thought that young women have a higher prevalence of basal-like subtype. Patients with luminal A type tumors live considerably longer before they develop metastatic disease. The basal-like subtype has been associated with poor clinical outcomes, and with a shorter relapse-free and overall survival than luminal tumors.

Basal-like breast cancers do not express ER, PR, or HER2, and therefore are not expected to benefit from antiestrogen therapies nor from trastuzumab. Basal-like tumors are defined by negative staining for ER, PR and HER2, and positive staining for cytokeratin 5, 6 and/or cytokeratin 14 and/or EGFR and/or cKIT, accumulation of p53 and with the proliferation marker Ki-67. BRCA1-associated breast carcinomas are usually of the basal-like subtype. The observation that BRCA1 mutations are strongly associated with a basal-like tumor phenotype indicates particularly poor prognosis in patients carrying this mutation.

Acknowledgements

The authors acknowledge the support of Pfizer Spain, which facilitated the necessary meetings to evaluate and discuss all the data presented in this review, and Dr.

Fernando Sánchez-Barbero from HealthCo SL (Madrid, Spain) for assistance in the preparation of this manuscript.


MD Montserrat Muñoz
email: mmunoz@clinic.ub.es

Quality of life during treatment in young women with breast cancer

Introduction

Health-related quality of life (HRQoL) is now considered an important endpoint in cancer clinical trials. Studies of HRQoL can indicate the directions needed for more efficient treatment of cancer patients. Among HRQoL studies in cancer patients, breast cancer has received most attention for several reasons. First, the number of women with breast cancer is increasing [START_REF] Stewart | World Cancer Report[END_REF]. Secondly, early detection and treatment of breast cancer have improved and survivors now live longer. Thirdly, surgery for breast cancer significantly affects a woman's self image and HRQoL studies can measure this.

HRQoL is a difficult concept to define because many key, essential, and intimate aspects of women are interlaced, such as health and fitness, emotional balance, family and social life, quality and grade of satisfaction of their sex lives, and preoccupations about their economy or future health. There are many tests or instruments that have been used in the context of cancer patients to measure the degree of impact on the HRQoL of the patient following the diagnosis or treatment of cancer. The most frequently used tests are the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its breast cancer specific complementary measure EORTC QLQ-BR23 [START_REF] Montazeri | Health-related quality of life in breast cancer patients: a bibliographic review of the literature from 1974 to 2007[END_REF]. Another is the Functional Assessment of Cancer Therapy in Breast (FACT-B) [START_REF] Montazeri | Health-related quality of life in breast cancer patients: a bibliographic review of the literature from 1974 to 2007[END_REF][START_REF] Brady | Reliability and validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life instrument[END_REF].

There are many other tests, some dealing with health and HRQoL and others that are more specific, measuring the degree of impact depending on the type of surgery performed or the treatment administered. A large number of studies have been published using all these instruments. The first article on HRQoL in breast cancer patients was published in 1974 [START_REF] Moore | Adrenalectomy with chemotherapy in the treatment of advanced breast cancer: objective and subjective response rates; duration and quality of life[END_REF]. In this historical study, patients with advanced breast cancer who underwent mastectomy with adjuvant chemotherapy were assessed for objective and subjective response rates, survival and HRQoL.

Impact of surgery on HRQoL

Traditional surgical outcomes, namely morbidity and mortality, remain important but are no longer sufficient on their own; the patient's perceptions of the impact of disease and treatment are increasingly being considered as integral to understanding health outcomes [START_REF] Revicki | FDA draft guidance and health-outcomes research[END_REF]. Breast conditions and their associated surgical interventions have a major impact on HRQoL. In fact, in specialties such as breast surgery it has been suggested that HRQoL must be the major, if not the only, end point [START_REF] Spilker | Quality of life considerations in plastic and reconstructive surgery[END_REF]. In spite of this, relatively little is known about the extent to which breast surgery impacts on HRQoL.

There are a number of reasons for this. First, there is a lack of detailed qualitative research based on inductive research methods and a paucity of quantitative research using valid, reliable, and responsive instruments to measure patient-reported outcomes in cosmetic and reconstructive breast surgery [START_REF] Pusic | Measuring quality of life in cosmetic and reconstructive breast surgery: a systematic review of patient-reported outcomes instruments[END_REF]. Second, few researchers have tried to understand exactly what it means to a woman having a breast condition, and the impact surgery will have on these perceptions. Third, breast conditions are varied and are associated with complex effects spanning the continuum of impact from physical functioning to social interaction. Therefore women with different conditions may experience the impact of these conditions differently. Initial treatment of primary breast cancer involves surgery to eradicate macroscopic disease, either before or after primary therapy. The extent of surgery (mastectomy vs. conservative) has an influence on the patient's self-image and self-perception which causes several effects. Patients who have undergone mastectomy have lowered body image and disturbances in their sexual life [START_REF] Engel | Quality of life following breast-conserving therapy or mastectomy: results of a 5-year prospective study[END_REF]. Nowadays, breast-conserving surgeries such as lumpectomy followed by radiotherapy, or breast reconstruction after mastectomy, are viable alternatives to mastectomy alone, especially in early stages of the disease [START_REF] Malata | Immediate breast reconstruction after mastectomy for cancer[END_REF]. Young patients, regardless of the type of surgery performed, show deterioration in their emotional and social life, with a great concern for their future health and economic problems. There are significant differences in aspects such as attractiveness, appearance or style of daily life [START_REF] Engel | Quality of life following breast-conserving therapy or mastectomy: results of a 5-year prospective study[END_REF]. When comparing the HRQoL of women younger than 50 years of age with women older than 50, the former experienced poorer emotional and social functioning, more concerns about future health and economic issues, although they also attained better scores in terms of physical and sexual activity. Different types of surgery do not appear to influence differently depending on age [START_REF] Engel | Quality of life following breast-conserving therapy or mastectomy: results of a 5-year prospective study[END_REF].

Al-Ghazal et al. [START_REF] Sk | Comparison of psychological aspects and patient satisfaction following breast conserving surgery, simple mastectomy and breast reconstruction[END_REF] compared the psychological outcome and satisfaction of patients who underwent wide local excision, mastectomy alone and mastectomy with breast reconstruction. They showed that significant statistical differences existed between the three procedures regarding satisfaction and psychosocial morbidity (anxiety, depression, body image, sexuality and self-esteem) with results in favour of wide local excision followed by breast reconstruction. They saw greatest morbidity in the mastectomy group. Patient satisfaction of cosmetic outcome and psychosocial aspects was greater in the wide local excision group than in the breast reconstruction or mastectomy groups [START_REF] Sk | Comparison of psychological aspects and patient satisfaction following breast conserving surgery, simple mastectomy and breast reconstruction[END_REF].

Impact of systemic treatment on HRQoL

Adjuvant chemotherapy and endocrine therapy reduce the risk of recurrence and death due to breast cancer, but often at considerable cost to the HRQoL of patients. The short-term side effects and negative influence on the HRQoL are known and in most cases are accepted by the majority of patients in return for modest gains in their prospects of recovery. The long-term side effects and their impact are poorly understood. Years after initial treatment, long-term side effects continue, especially vasomotor symptoms and altered sexual function [START_REF] Grimison | Quality of life and adjuvant systemic therapy for early-stage breast cancer[END_REF].

Information regarding HRQoL is helpful in describing and grading the most common effects of adjuvant treatment, facilitating informed decision-making, identifying health problems to guide research into potential solutions, guiding treatment strategies for interventions with equivalent survival and guiding resource allocation. New technologies will make HRQoL information increasingly available for individual patient care [START_REF] Grimison | Quality of life and adjuvant systemic therapy for early-stage breast cancer[END_REF].

Chemotherapy is the treatment that most adversely affects the HRQoL of patients.

Patients treated with mastectomy and adjuvant chemotherapy are those with greater impairment. Ganz et al. [START_REF] Ganz | Quality of life at the end of primary treatment of breast cancer: first results from the moving beyond cancer randomized trial[END_REF] did not detect deterioration in mental status scores despite the complexity of the treatment administered to more than half of the women included in the study. At the end of primary treatment for breast cancer, women reported good emotional functioning, but with decreased physical functioning, particularly women who had undergone mastectomy or received chemotherapy.

In another study, Ganz et al. [START_REF] Ganz | Breast cancer in younger women: reproductive and late health effects of treatment[END_REF] showed that overall HRQoL in younger women who had survived breast cancer was good, but there was evidence of increased emotional disruption, especially among the youngest patients. Factors that may contribute to poorer health perceptions and HRQoL include experiencing a menopausal transition as part of therapy, and feeling more vulnerable after cancer.

Impacts on HRQoL may vary according to the type of systemic regimen. A study by the

Grupo Español de Investigación del Cáncer de Mama (GEICAM) [START_REF] Martin | Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen[END_REF] comparing docetaxel, doxorubicin and cyclophosphamide (TAC) versus 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) in node-positive patients reported that the deterioration in the HRQoL in patients receiving taxanes was higher than in those receiving FAC. This effect disappeared after approximately 6 months of having completed the systemic treatment.

The end of treatment can be exceedingly stressful for women with breast cancer, especially for those who have received adjuvant chemotherapy and/or radiation treatments [START_REF] Beisecker | Side effects of adjuvant chemotherapy: perceptions of node-negative breast cancer patients[END_REF][START_REF] Ward | Patients' reactions to completion of adjuvant breast cancer therapy[END_REF]. In a study including 160 lymph node-negative breast cancer survivors, women were asked, between 4 and 12 months after the end of treatment, to rate stressful aspects of their cancer experience. Ending radiation therapy and ending chemotherapy were rated as moderately to extremely stressful for 27% and 48% of the women, respectively [START_REF] Green | Prevalence of posttraumatic stress disorder in women with breast cancer[END_REF]. A number of variables appear to contribute to the stress of this transition period. First, women report fear of recurrence after active treatment is withdrawn, because patients may feel as though a safety net has been lost [START_REF] Ward | Patients' reactions to completion of adjuvant breast cancer therapy[END_REF].

Second, many survivors report being unprepared for the lingering side effects of therapy such as fatigue, alopecia, and menopausal symptoms [START_REF] Beisecker | Side effects of adjuvant chemotherapy: perceptions of node-negative breast cancer patients[END_REF].

Sexual activity in breast cancer patients

According to the study by Ganz et al. [START_REF] Ganz | Quality of life at the end of primary treatment of breast cancer: first results from the moving beyond cancer randomized trial[END_REF] 60% of patients reported being sexually active at the end of their breast cancer treatments, and this proportion was higher among women who had received chemotherapy than in patients who had received surgery alone, probably because of the relationship between age and the administration of a less aggressive treatment. Over 50% of young women said that chemotherapy had a negative effect on their sex life. Women who were most likely to report a negative impact on sexuality from cancer were those who had experienced changes in hormonal status, problems in their relationships, and difficulties with vaginal dryness [START_REF] Ganz | Quality of life at the end of primary treatment of breast cancer: first results from the moving beyond cancer randomized trial[END_REF]. There are other many complex circumstances that may contribute to cessation of sex; these include lack of a partner, fatigue, loss of libido, disinterest or physical problems of the partner.

Conclusions

Young women have a wider variety of aspects of HRQoL than older women during and after breast cancer treatment. Patients who have undergone mastectomy have worse body image and disturbances in their sexual life. Other surgical treatmentssuch as breast-conserving surgeries are viable alternatives to mastectomy and have a better impact on HRQoL. Chemotherapy is the treatment that most adversely affects the HRQoL of patients. Fatigue, alopecia, and menopausal symptoms are some of the chemotherapy-related side effects that impact greatly on HRQoL. Patients treated with mastectomy and adjuvant chemotherapy are those with the greatest impairment. Also, sexual activity is negatively affected by chemotherapy. Psychological intervention for these women and their families significantly helps young women with breast cancer to cope successfully with this disease.

Acknowledgements

The authors acknowledge the support of Pfizer Spain, which facilitated the necessary meetings to evaluate and discuss all the data presented in this review, and Dr.

Fernando Sánchez Barbero from HealthCo SL (Madrid, Spain) for assistance in the preparation of this manuscript.


Juan De La Haba

Milagros Calderay
email: mcalderay@gmail.com

MD Milagros Calderay Domínguez

Impact of breast cancer treatment on fertility

Introduction

Approximately 25% of breast cancers occur in premenopausal women, and 15% occur in women younger than 45 years of age [START_REF] Hankey | Trends in breast cancer in younger women in contrast to older women[END_REF]. Because the average age of first pregnancy is rising, the percentage of women diagnosed with breast cancer that are of childbearing age or pregnant is also increasing. In addition, the possibility of a woman willing to become pregnant after breast cancer treatment is also rising.

There are no studies showing that later pregnancy has a negative effect on the survival of patients who have been diagnosed and treated for breast cancer. A recent review concluded that there was no adverse effect, and perhaps even a slight protective effect, on survival by childbearing after breast cancer treatment [START_REF] Gelber | Effect of pregnancy on overall survival after the diagnosis of early-stage breast cancer[END_REF]. The superior survival seen in this and other controlled studies may merely reflect a bias towards the selection of healthy patients, but it is also consistent with a potential antitumor effect of pregnancy [START_REF] Gelber | Effect of pregnancy on overall survival after the diagnosis of early-stage breast cancer[END_REF].

The increased survival and decreased mortality of breast cancer patients is partly due to the use of screening programs that allow an earlier diagnosis, and the improvement of treatments, including chemotherapy and hormone therapy [START_REF] Sonmezer | Fertility preservation in young women undergoing breast cancer therapy[END_REF]. Most cancer therapies have a substantial morbidity on reproductive function, not only because they increase the risk of early menopause, but also because they are associated with a decreased ovarian reserve and a lost of fertility. The impact of infertility on the quality of life of the patient who survives breast cancer explains the increase in the demand for fertility preservation techniques [START_REF] Sonmezer | Fertility preservation in young women undergoing breast cancer therapy[END_REF].

Chemotherapy-induced amenorrhea (CIA)

The effects of chemotherapy are reversible in most organs, but not in ovarian tissue. In a significant number of premenopausal women, the administration of adjuvant chemotherapy induces a state of amenorrhea, in many cases irreversible depending on the extent of tissue damage and prior ovarian reserve, which has important short-and long-term implications [START_REF] Ganz | Menopause and breast cancer: addressing the secondary health effects of adjuvant chemotherapy[END_REF] (Table 1). Chemotherapy causes a progressive dose-relate depletion of ovarian follicles and granulosa cells that translates into oligo-amenorrhea and subsequent premature ovarian failure, ultimately leading to what is known as CIA. [START_REF] Warne | Cyclophosphamide-induced ovarian failure[END_REF]. From an endocrine point of view, a decrease in estrogen levels with elevated follicule-stimulating hormone (FSH) and luteinizing hormone (LH) levels occurs (i.e.

hypergonadotropic hypogonadism).

While there is significant variability in the definition of CIA, some retrospective and prospective studies have reviewed the factors involved in its onset and the degree of reversibility [START_REF] Poikonen | Prognostic effect of amenorrhoea and elevated serum gonadotropin levels induced by adjuvant chemotherapy in premenopausal node-positive breast cancer patients[END_REF][START_REF] Tormey | Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial[END_REF][START_REF] Goldhirsch | The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. The International Breast Cancer Study Group[END_REF][START_REF] Pagani | Prognostic impact of amenorrhoea after adjuvant chemotherapy in 12 premenopausal breast cancer patients with axillary node involvement: results of the International Breast Cancer Study Group (IBCSG) Trial VI[END_REF][START_REF] Richards | Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's/Manchester trial[END_REF]. The exact incidence of CIA is difficult to establish because many factors can contribute to it, but the type of chemotherapy, cumulative dose and the patient's age are the main factors that determine the occurrence of CIA. Following chemotherapy, older women have a higher incidence of complete ovarian failure and permanent infertility compared with younger women [START_REF] Sonmezer | Fertility preservation in young women undergoing breast cancer therapy[END_REF][START_REF] Marhhom | Fertility preservation options for women with malignancies[END_REF], and it is estimated that the physiological age of the ovaries in a cancer survivor may be 10 years older than the actual chronological age [START_REF] Mastro | Infertility and pregnancy after breast cancer: current knowledge and future perspectives[END_REF]. Therefore, regardless of the beneficial effects that hormonal changes can have as part of the adjuvant endocrine strategy, CIA is an adverse event to take into account for the selection of the best adjuvant treatment.

The abolition of menstruation due to the use of alkylating agents is probably the most reviewed subject in the scientific literature. For patients in whom drugs such as melphalan or cyclophosphamide are used, reported CIA rates range from 25 to 95% respectively [START_REF] Brincker | Evidence of a castration-mediated effect of adjuvant cytotoxic chemotherapy in premenopausal breast cancer[END_REF]. These rates were lower in younger patients and higher when the number of cycles or dosage was increased [START_REF] Pagani | Prognostic impact of amenorrhoea after adjuvant chemotherapy in 12 premenopausal breast cancer patients with axillary node involvement: results of the International Breast Cancer Study Group (IBCSG) Trial VI[END_REF]. Chemotherapeutic agents can be grouped into three risk groups according to their potential to cause ovarian damage [START_REF] Oktay | Fertility preservation in gynecologic cancers[END_REF]:

1. High Risk: Cyclophosphamide, melphalan, busulfan, chlorambucil, procarbazine and nitrogen mustard are alkylating agents that are associated with an increased risk of ovarian failure, with an overall response of 3.98 compared to unexposed women [START_REF] Demeestere | Preliminary experience of ovarian tissue cryopreservation procedure: alternatives, perspectives and feasibility[END_REF]. Regarding specific group data, there are conflicting results regarding the ability of anthracyclines to increase the rate of CIA when these are used in combination with alkylating agents. Thus, in the MA.5 study comparing cyclophosphamide, methotrexate, and fluorouracil (CMF) versus cyclophosphamide, epirubicin, and fluorouracil (CEF), there were higher rates of amenorrhea in women who received anthracyclines (76% vs 64%; p=0.03), although higher doses of alkylating agents were received in the CMF arm [START_REF] Parulekar | Incidence and prognostic impact of amenorrhea during adjuvant therapy in high-risk premenopausal breast cancer: analysis of a National Cancer Institute of Canada Clinical Trials Group Study--NCIC CTG MA.5[END_REF]. By contrast, in a trial comparing four cycles of doxorubicin and cyclophosphamide (AC) versus six cycles of CMF, the highest percentage of CIA (>12 months) occurred in the CMF arm (34% vs 69%) [START_REF] Goodwin | Risk of menopause during the first year after breast cancer diagnosis[END_REF]. Age was the most important predictor of CIA in all these studies. For women older than 40 years treated with anthracyclines, CIA rate was 95%, compared with 30% in women younger than 40 years.

Other studies have analyzed how the dose and duration of anthracyclines impact on ovarian suppression. The Cancer and Leukemia Group B study (CALGB 8541), which compared three doses of adriamycin (30, 40 and 60 mg/m 2 ), found no differences in rates of CIA [START_REF] Budman | Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B[END_REF]. In the French Adjuvant Study Group 01 trial (FASG), three different doses of epirubicin were compared with different numbers of cycles. A relationship between CIA and the cumulative dose of anthracyclines was found [START_REF] Fumoleau | Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial[END_REF]. Again, the results are contradictory when the relationship with dose density is studied, especially when maintaining the same cumulative dose of anthracyclines.

Taxanes are another group of drugs that have been analyzed for this toxicity. For sequential schedules, CIA rates are very similar in patients older than 40 years (85%).

However, there are differences in younger women. A study that compared the same number of cycles of fluorouracil, doxorubicin and cyclophosphamide (FAC) with docetaxel, doxorubicin and cyclophosphamide (TAC) showed that the percentage of amenorrheic patients was higher in the arm that received docetaxel (62% vs 52%; p=0.007) [START_REF] Martin | Adjuvant docetaxel for node-positive breast cancer[END_REF]. Table 2 shows a summary of studies which have evaluated the incidence of CIA according to different chemotherapy schedules.

The relationship between tamoxifen and amenorrhea is well established, although tamoxifen monotherapy carries a low risk of CIA, which largely depends on the patient's age [START_REF] Swain | Amenorrhea in premenopausal women on the doxorubicin-andcyclophosphamide-followed-by-docetaxel arm of NSABP B-30 trial[END_REF]. The possible mechanism could be an increase in serum estrogen levels and a blockade of the hypothalamic-ovarian axis.

Studies to identify women with diminished ovarian reserve could include measurement of follicle-stimulating hormone, inhibin B or anti-Müllerian hormone levels, or a transvaginal ultrasound to determine the number of antral follicles. Serum anti-Müllerian hormone may be a promising marker of ovarian reserve in women after breast cancer treatment because its level decreases with age and in younger patients who survive cancer; other possibilities include measurement of inhibin B levels and antral follicle count [START_REF] Mastro | Infertility and pregnancy after breast cancer: current knowledge and future perspectives[END_REF].

Strategies to preserve fertility

Young women diagnosed with breast cancer need to be advised by a multidisciplinary team on the impact of treatment on subsequent fertility before starting any treatment, and should be provided with access to specialized units that help them to preserve their fertility.

The choice of the method of preserving fertility depends on the patient's age, her desire to become pregnant, the type of chemotherapeutic treatment to be administered, the time available before chemotherapy commences, the amount of time pregnancy must be delayed after treatment, and the potential for the cancer to metastasize to the ovary [START_REF] Sonmezer | Fertility preservation in young women undergoing breast cancer therapy[END_REF][START_REF] Lee | American Society of Clinical Oncology recommendations on fertility preservation in cancer patients[END_REF].

Embryo and oocyte cryopreservation

Embryo cryopreservation is currently the only clinically tested procedure. Nevertheless, this approach has several limitations because a partner or a sperm donor is required, and ovarian stimulation is necessary, which may delay the start of chemotherapy by 2-6 weeks, a situation which may not always be advisable. Overriding all these considerations, however, are the ethical and legal problems associated with embryo cryopreservation [START_REF] Sonmezer | Fertility preservation in young women undergoing breast cancer therapy[END_REF][START_REF] Bankowski | The social implications of embryo cryopreservation[END_REF].

Oocyte cryopreservation is an emerging option for preserving fertility in women without partners who do not wish to use donor semen. This procedure also requires ovarian stimulation. The rapid freezing technique of vitrification has presented a breakthrough in oocyte cryopreservation. This technique is fast, safe, effective and less costly. Given the high survival rates, together with the high fertilization rates and better results in terms of healthy births, vitrification is the method of choice for oocyte cryopreservation [START_REF] Kim | Fertility preservation in female cancer patients: current developments and future directions[END_REF]. The advantages of oocyte cryopreservation are that it requires minimal invasion, oocytes can be preserved for an unlimited time and there is no need for a sperm sample. On the other hand, this method does not maintain hormonal function and is applicable only during childbearing years.

Both embryo and oocyte cryopreservation require ovarian stimulation, but in the case of hormone-dependent breast cancer, the increased estrogen levels produced by ovarian stimulants could contribute to the proliferation of tumor cells and hence should be avoided. To minimize exposure to estrogens, two strategies have been suggested: an unstimulated/natural cycle, and the use of chemoprotective agents with low-dose protocol of in vitro fertilization. The efficacy of natural cycle techniques is hampered by high rates of a premature rise in LH levels and premature ovulation [START_REF] Pelinck | Efficacy of natural cycle IVF: a review of the literature[END_REF]. Tamoxifen and aromatase inhibitors appear to be the best candidates for ovarian stimulation because of both their effectiveness in preventing breast cancer recurrence and their ability to induce ovulation [START_REF] Sonmezer | Fertility preservation in young women undergoing breast cancer therapy[END_REF][START_REF] Casper | Aromatase inhibitors in ovarian stimulation[END_REF].

Ovarian cryopreservation

This technique allows the storage of a large number of primordial follicles for long periods of time before subsequent reimplantation of the preserved ovarian material. It has potential advantages over embyro and oocyte cryopreservation as it can be carried out at any time, does not require ovarian stimulation and does not delay the start of chemotherapy. It is indicated in patients with breast cancer in whom treatment must be started immediately and who therefore cannot undergo ovarian stimulation, as well as in girls and in women for whom sperm donation is unacceptable [START_REF] Donnez | Ovarian tissue cryopreservation and transplantation in cancer patients[END_REF].

Compared to whole ovary cryopreservation, ovarian cortical slice cryopreservation is the preferred technique. It is advisable to analyze samples to confirm the presence of follicles and the absence of metastases. There are several strategies to bring about maturation of oocytes after treatment for cancer such as autotransplantation (orthotopic or heterotopic), xenotransplantation and maturation in vitro [START_REF] Kim | The future of human ovarian cryopreservation and transplantation: fertility and beyond[END_REF]. To date, five studies of children born after reimplantation of cryopreserved ovarian tissue have been reported.

The number of reimplantations performed by all groups was relatively low due to the amount of time between implantation and the age at which the dissection procedure originally took place [START_REF] Novella-Maestre | Estadop actual de la congelación de la corteza ovárica[END_REF].

The biggest problem of this technique is that revascularization of the transplanted tissue occurs after several days with consequent ischemia that may induce partial fibrosis and loss of primordial follicles. Another problem that should be considered with autotransplantation of ovarian tissue in women with cancer is the possibility of transmitting microscopic metastatic disease. Advantages of this technique are the recovery of hormonal function and the possibility of pregnancy.

Use of gonadotropin-releasing hormone-analogues (GnRH-a)

During treatment with chemotherapy, the use of GnRH-a as the only method to preserve fertility is highly controversial. There are several proposed mechanisms of action to explain the protective action of GnRH-a, including suppression of FSH secretion and decrease in uterine and ovarian blood flow, with a subsequent decrease in the number of primordial follicles exposed to chemotherapy [START_REF] Tocino | Uso de los análogos de la GnRH en la preservación de la fertilidad[END_REF].

There are a limited number of studies supporting the use of GnRH-a to prevent ovarian failure in humans, which have been criticized for the lack of randomization, control groups and follow-up periods [START_REF] Gerber | Controversies in preservation of ovary function and fertility in patients with breast cancer[END_REF]. Moreover, GhRH-a causes a prepubertal hormonal situation in adult women, but prepubescent girls who receive high doses of chemotherapy continue to suffer from ovarian failure. Another reason not to recommend the use of GhRH-a is because it causes tumor cells to stop in G0 phase of the cell cycle, making them less sensitive to chemotherapy [START_REF] So | Gonadotropin-releasing hormone and ovarian cancer: a functional and mechanistic overview[END_REF]. Definitive evidence of the role of GhRH-a in preserving ovarian function is under evaluation in phase III trials [START_REF] Gerber | Controversies in preservation of ovary function and fertility in patients with breast cancer[END_REF][START_REF] Manger | Prevention of gonadal toxicity and preservation of gonadal function and fertility in young women with systemic lupus erythematosus treated by cyclophosphamide: the PREGO-Study[END_REF]. We believe that GnRH-a should not be offered as the sole method of fertility preservation until the efficacy in protecting ovarian function is fully demonstrated [START_REF] Lee | American Society of Clinical Oncology recommendations on fertility preservation in cancer patients[END_REF].

Conclusions

Most cancer therapies used have substantial morbidity on later reproductive capacity, not only increasing the risk of early menopause but also decreasing ovarian reserve and loss of fertility. CIA is an important adverse event to take into account in young women when selecting the best adjuvant endocrine strategy. According to the Ethics Committee of the American Society for Reproductive Medicine, physicians should inform cancer patients about their reproductive future and options to preserve fertility prior to treatment.

The only clinically established method for fertility preservation is embryo cryopreservation. Experimental procedures such as oocyte and ovarian tissue cryopreservation and GnRH-a should only be offered as part of a clinical trial protocol.

CIA is a highly complex adverse event that requires close attention, especially with the advent of new chemotherapeutic agents.

2 .

 2 Moderate Risk: Cisplatin causes ovarian failure with an overall response of 1.77. Doxorubicin and paclitaxel also fall into this group. 3. Low risk or no risk: Methotrexate, 5-fluorouracil, bleomycin and actinomycin D, and vinca alkaloids cause ovarian failure with an overall response of about 1.

  and cyclophosphamide; CEF: cyclophosphamide, epirubicin, and fluorouracil; CMF: cyclophosphamide, methotrexate, and fluorouracil; P: paclitaxel; T: docetaxel; FAC: 5-fluorouracil, doxorubicin and cyclophosphamide; TAC: docetaxel, doxorubicin and cyclophosphamide.

Table 1 .

 1 Side effects of amenorrhea.

	Side effects of amenorrhea
	Osteoporosis
	Arthralgia
	Increased cardiovascular morbidity
	Hot Flushes
	Genitourinary dysfunctions
	Sexual dysfunctions
	Sterility
	Insomnia
	Anxiety
	Depression

Table 2 .

 2 Incidence of chemotherapy-induced amenorrhea according to different chemotherapy schedules.

	Author	Treatment regimen	Nº Cycles Age % of Amenorrhea
			>40	90
	Castiglione [34]	CMF	6
			≤40	50
			>40	96
	Bonadonna [35]	CMF	12
			≤40	40
			>40	76
	Roche [36]	CEF	6
			≤40	38
	Berliere [37]

Acknowledgements

The authors acknowledge the support of Pfizer Spain, which facilitated the necessary meetings to evaluate and discuss all the data presented in this review, and Dr.

Fernando Sánchez Barbero from HealthCo SL (Madrid, Spain) for assistance in the preparation of this manuscript.


J G Vián
email: vian@unavarra.es

D Astrain

DEVELOPMENT OF A HYBRID REFRIGERATOR COMBINING THERMOELECTRIC AND VAPOR COMPRESSION TECHNOLOGIES

Keywords: thermoelectricity, computational model, refrigeration, Peltier, vapor compression

A domestic refrigerator with three compartments has been developed: Refrigerator compartment, at 4ºC (vapor compression cooling system); freezer compartment, at -22ºC (vapor compression cooling system); and a new super-conservation compartment, at 0ºC (thermoelectric cooling system). The thermoelectric system designed for the superconservation compartment eliminates the oscillation of its temperature due to the start and stop compressor cycles, obtaining a constant temperature and thus, a better preservation of the food.

For the design and optimization of this application, a computational model, based in the numerical method of finite differences, has been developed. This model allows to simulate the complete hybrid refrigerator (vapor compression -thermoelectricity). The accuracy of the model has been experimentally checked, with a maximum error of 1.2ºC for temperature values, and 8% for electric power consumption.

By simulations with the computational model, the design of the refrigerator has been optimized, obtaining a final prototype highly competitive, by the features on food preservation and power consumption: 1.15kWh per day (48.1W) for an ambient temperature of 25ºC. According to European rules, this power consumption value means that this new refrigerator could be included on energy efficiency class B.

INTRODUCTION

The cold production is based in a refrigerating machine, with a well known principle of operation. A heat flux is absorbed from a room, and evacuated to the exterior. To make this possible, an energy contribution is needed. There are four main cooling systems: vapor compression, absorption, gas and thermoelectricity. In the absorption systems the energy supply is by a heat flux, in vapor compression and gas is a mechanical power and in the thermoelectric systems is by an electric power.

In domestic refrigerators, the most used cooling system is vapor compression, as it has a good value of C.O.P. However, the control of the temperature inside the cooled compartment is inaccurate, as the compressor makes start and stop cycles, what makes a oscillation in the temperature higher than 8ºC, as shown in [START_REF] He | Testing of the mixing refrigerants HFC152a/HFC125 in domestic refrigerator[END_REF]. This fact has a very damaging effect in the preservation of the food, especially in fishes, meats and fruits.

There are some domestic refrigerators with a new compartment, where the temperature is close to 0ºC to improve the preservation of the food. However, as the cooling system is vapor compression, the temperature oscillates significantly (due to the start and stop cycles) not reaching the objective of a proper preservation.

On the other hand, there are thermoelectric refrigerators presented in [START_REF] Gao Min | Experimental evaluation of prototype thermoelectric domesticrefrigerators[END_REF], [START_REF] Astrain | Increase of COP in the thermoelectric refrigeration by the optimization of heat dissipation[END_REF], and [START_REF] Jancsurak | Green refrigerator is like no other[END_REF] with a good control in the temperature of the compartment and, thus, a better preservation of the food. This is due to the fact that it is possible to modify the supplied voltage to the Peltier modules to adjust the cooling power as needed. In addition, these devices are more compact and quiet because they have no moving parts. However, the cooling system has a lower value of C.O.P and thus, high power consumption.

In this work we have developed a domestic refrigerator that combines both technologies (thermoelectricity and vapor compression) in order to join the good C.O.P. values of the vapor compression system with the excellent control of the inside temperature of thermoelectric technology. The prototype is based on a domestic Combi refrigerator (bottom freezer), which includes a new super-conservation compartment, cooled by thermoelectricity.

OBJECTIVES.

The main objective of this work is to develop a hybrid domestic refrigerator that combines the cooling technologies of vapor compression and thermoelectricity. This refrigerator will have the following compartments: a. Freezer compartment at -20ºC, with vapor compression cooling system. b. Refrigerator compartment at 5ºC, with vapor compression cooling system. c. Super-conservation compartment at 0ºC, with thermoelectric cooling system.

The maximum oscillation of the temperature is 0.5ºC.

In order to meet this objective the following specific objectives have been planned:

-Development of a computational model that simulates the complete hybrid refrigerator.

-Adjustment and validation of the computational model.

-Design and optimization of the hybrid refrigerator.

DESCRIPTION AND OPERATION OF THE HYBRID REFRIGERATOR.

The prototype is based on a commercial domestic refrigerator from Bosch-Siemens, BOSCH KGF-39, with two compartments: refrigerator compartment, with its temperature oscillating around 5ºC; and freezer compartment, with its temperature oscillating around -20ºC. Each compartment has an independent cooling vapor compression system. A new compartment of super-conservation, with a constant temperature of 0ºC and a maximum temperature oscillation of 0.5ºC, is added to this refrigerator. This new compartment is placed in the middle of the refrigerator, as shown in Figure 1, and has a thermoelectric technology based cooling system (TEC), [START_REF] Gao Min | Experimental evaluation of prototype thermoelectric domesticrefrigerators[END_REF], [START_REF] Astrain | Computational model for refrigerators based on Peltier effect application[END_REF]. Dimensions and volumes of every compartment are presented in Table 1, along with the thickness values of all the walls. In the development of the hybrid refrigerator, we considered two different configurations for the thermoelectric modules that control the temperature inside the superconservation compartment.

Configuration I

In this configuration, the Peltier modules are placed in the rear wall of the superconservation compartment, as shown in Figure 1. Thus, when an electric power is supplied to the Peltier modules, these absorb the heat flux from the interior of the compartment and throw it to the exterior. To make this happen, the thermoelectric system has: Peltier modules, a cold extender (that separates the hot side from the cold side), a cold plate (that connects the cold side of the Peltier module and the air inside), and a dissipater (that helps to evacuate the heat absorbed from the inside plus the electric power supplied).

This configuration has the inconvenience that, as the heat from the hot side of the Peltier module is thrown directly to the exterior, the temperature gap between the faces of the Peltier module is higher than 30ºC. A consequence of this is that the C.O.P. of the thermoelectric device is very low, as demonstrated in [START_REF] Gao Min | Experimental evaluation of prototype thermoelectric domesticrefrigerators[END_REF] and [START_REF] Astrain | Computational model for refrigerators based on Peltier effect application[END_REF].

One way to improve the C.O.P. value is to make lower the value of the thermal resistance of the heat exchanger on the hot side of the Peltier module. This was achieved by developing a phase-change thermosiphon, [START_REF] Astrain | Increase of COP in the thermoelectric refrigeration by the optimization of heat dissipation[END_REF]. If configuration 1 was chosen, this phase-change thermosiphon would be used.

Configuration II

In order to decrease the temperature gap between the faces of the Peltier module, this new configuration was designed. The thermoelectric device is placed in the wall between the refrigerator and super-conservation compartments, as shown in Figure 1, configuration II. The heat flux from the hot side of the Peltier modules is introduced in the refrigerator compartment, where is absorbed by the evaporator and thrown to the exterior thanks to the vapor compression cooling system, which has a good COP value (approximately 1). It is a cascade refrigeration system that combines thermoelectricity and vapor compression.

The advantage of this configuration is that the temperature gap between the sides of the Peltier modules is decreased, as the heat exchanger of the hot side is in contact with air at 5ºC. This means a significant improvement of the COP, as is shown in advanced.

COMPUTATIONAL MODEL

In order to make a study of this new application, a computational model has been developed. This model simulates the behavior of the complete hybrid refrigerator with the three compartments and their cooling systems. The inputs of the model are: materials and geometry of the refrigerator, type of Peltier modules (dimensions and materials), electric power supplied to the Peltier modules, thermal resistance of both the hot side dissipater and the cold side dissipater, and the average cooling power of the evaporator in both the refrigerator compartment and the freezer compartment. After the simulations, the model provides the following outputs: temperatures of all the elements and compartments as a function of time, heat fluxes, power consumptions and COP of both the thermoelectric device and the hybrid refrigerator. This model is based on a previous model that was developed for thermoelectric refrigerators. Some results are shown in [START_REF] Astrain | Computational model for refrigerators based on Peltier effect application[END_REF]. This previous model has been properly modified to this new application of hybrid refrigeration.

The model solves the following equations of the thermoelectric effects (Seebeck, Peltier and Joule) [START_REF] Rowe | CRC Handbook of Thermoelectrics[END_REF], as well as the heat conduction in transitory state:

   AB AB A B dE dT    (1)
 

Q I I T P AB B A .         (2) q J J .  2  (3)     . . ( ) * c t k t q p     (4)
To simplify the model some hypothesis were taken to account:

-Materials are isotropic.

-The Thompson effect has been neglected by the Peltier and Joule effects as

shown in [START_REF] Rowe | Modern Thermoelectrics[END_REF].

For the numeric solution of equation ( 4) the implicit finite difference method has been used. For the one-dimension case, the next step temperature at node i, t i ', can be calculated as a function of the present temperature at node i and the next step temperatures on the close nodes.

In order to simulate the two configurations, a discretization and modelization of both of them were made.

In Figure 2 The temperatures of the nodes of Figure 2 and 3 are described in the nomenclature. In the discretization, each node represents a volume with a thermal resistance and a thermal capacity. These values are obtained by using the following general expressions:

A k L R .  (5) p c V C . .  (6)
Some thermal resistances, as the insulator walls (R cong , R te , R r te , R tec , and R ref ), where the convection appears in addition to the conduction effect, are calculated by using the following equation:

R U S ais  1 . ( 7
)
Where S is the surface and U is the global heat transfer coefficient between the interior and the exterior of each compartment, obtained from the equation:

U h e k h ext    1 1 1 int (8)
To calculate the internal and external convection coefficients, the equation experimentally checked by G.V. Parmelee in [START_REF] Parmelee | Heat Transfer by Forced Convection Along a Smooth Flat Surface[END_REF] for a plate was used. Viscous dissipation was neglected and laminar flow was assumed, since the air velocity is low:

Nu L L x c             0
The contact resistance between the Peltier module and the heat extender has been obtained from the Ritzer and Lau work (1994) [START_REF] Ritzer | Economic Optimization of Heat Sink Design, 13th International Conference on Thermoelectrics[END_REF], which provides a value of 0.03K/W.

In the Peltier module, in addition to the thermal capacities and resistances, there are heat sources due to the thermoelectric effects, equations ( 2) and (3). As an example, the equations for the discretization of node 6 in Figure 3 are the following ones. This node is an internal node of the Peltier module.

 

t t c q R t t R t t             (10)
q t c t c R R R t R t                     (11)
q c t t c R R c t R c t R c                        (12) 6 6 6 7 67 6 6 67 56 6 5 56 6 1 1 1 1 1 q c t t R c t R R c t R c                             (13)
Where q 6 represents the heat generation due to the Joule effect, described in equation (3); c 6 is the thermal capacitance obtained by using equation ( 6); R 56 and R 67 are the thermal resistances between the nodes 5-6 and 6-7, from equation (5); t 6 and t 7 represent the temperature of the nodes 6 and 7 in the time step  ; t' 5 , t' 6 and t' 7 represent the temperature of nodes 5, 6 and 7 in the time step +.

Proceeding in the same way with the rest of the nodes of the discretization presented above in Figure 2 and3, two matrix systems (one for each configuration) like the following one are obtained:

      M T T C Q i i i i . ' . .          ( 14
)
The system is non linear as the heat fluxes from the thermoelectric effects (equations 2 and 3) depend on the temperature. Thus, it has been solved using an iterative method, which uses the temperatures and heat fluxes from the n time step to calculate the temperatures of the n+1 time step. Also, [M] matrix and

Q i .      
vector must be recalculated in every step.

RESULTS AND DISCUSSION

Validation of the computational model

Once the computational model was developed and the first prototype was built (configuration II), we proceeded to validate experimentally the computational model and to calculate its accuracy.

Several thermocouples were placed in the prototype: hot and cold side of the Peltier module; freezer, super-conservation and refrigerator compartments; and ambient.

In Figure 4, we compare the temperatures of the first prototype with the simulated temperatures given by the computational model, when the ambient temperature is 30ºC and the Peltier module supplied voltage is 4V.

It can be seen that, when steady state is reached, the experimental temperatures of the three compartments are close to the temperatures predicted by the model. However, the temperatures of the different elements of the hybrid refrigerator drop quicker than the model predicts. This is because the cooling power is introduced in the model as a mean value obtained from the following equation: Where:

Mean Cooling Power: is the cooling power (Watts) and would represent the equivalent cooling power of the vapor compression system, if it worked the whole day without stopping. It is an input of the model.

Real Compressor Cooling Power: is the real cooling power (Watts) of the vapor compression system when it works normally.

Operational relation: number of hours per day that the compressor works, divided by 24 hours.

However, the compressor works with start and stop cycles. When the hybrid refrigerator is working, the compressor of the refrigerator compartment works at full power until the thermostat turns it off. The mathematical model does not represent this behavior but it simulates the compressor as working at mean cooling power all the time. This fact also explains why in the simulations there are no cycles on the temperatures, as shown in Figure 4. A resume of these results is shown in Table 2 for steady state, comparing the experimental and simulated results for the first prototype and the computational model.

The good accuracy of the model can be seen. It predicts temperature values with a maximum error of 1.2ºC and the electric power consumption of the cooling system with a maximum error of 8.3%.

Results of the simulations using the model for different configurations of hybrid refrigerators.

After the accuracy of the computational model was checked, the model was used as a design and optimization tool of the hybrid domestic refrigerator (vapor compressionthermoelectricity).

In the first study, we analyzed which configuration (see Figure 1) was better from a thermal point of view. In order to complete this study, both configurations were simulated under the same conditions. The results of these simulations are shown in Table 3, where can be seen the electric power consumption of the freezer compressor, of the refrigerator compressor and of the thermoelectric modules, for two different ambient temperatures (25ºC and 30ºC). The total hybrid refrigerator power consumption and all the temperatures for both configurations are presented as a function of the thermal resistances of the dissipaters in the hot and the cold side of the Peltier modules. Tte (ºC)

0,0 0,0 0,0 0,0 0,0 0,1 0,0 0,0 COPte 1,2 1,3 1,4 2,0 1,0 1,1 1,1 1,7
Pref (W) These results show that configuration II is more efficient from an energetic point of view, since it needs 80% less electric power consumption than configuration I. This is due to the fact that, as the thermoelectric system is operating in cascade with the vapor compression system, the temperature of the hot side of the Peltier module is closer to the cold side, what makes the COP value greater (near 1 for configuration II against 0.1 for configuration I). It means that, for configuration II, the Peltier modules should be supplied with a lower voltage (3V against 12V for configuration I) what makes a lower power consumption (6.5W against 99.6W, for 25ºC ambient temperature). This advantage of configuration II makes the total electric power consumption of the appliance lower, although the power consumption of refrigerator compressor is greater (24.3W against 13.6W for configuration I), since the heat flux from the hot side of the Peltier module is absorbed by the evaporator of the refrigerator compartment.

Besides, configuration I is not capable of reaching 0ºC in the thermoelectric compartment, even if the Peltier modules are supplied at full power, as can be seen in Table 3. Thus, configuration II was elected.

Another conclusion from the analysis of the results from Table 3 is the significant influence of the thermal resistance of the dissipaters of the thermoelectric system on the global behavior. For example, for configuration I, when reducing the thermal resistance of the hot side from 0.35K/W to 0.15K/W, the temperature of the thermoelectric compartment decreases 4.1ºC. For configuration II, the same improvement in this thermal resistance makes a decrease of 65% in power consumption.

To optimize the system, simulations studying the possibility of using thermal bridges between the freezer and the super-conservation compartments were made. These thermal bridges are aluminum slabs that connect both compartments. The objective of these devices is making the freezer absorb the maximum heat flux from the thermoelectric compartment as possible, in order to keep the temperature of this compartment at 0ºC (design temperature). By doing this, the power consumption of the Peltier modules could be reduced.

The results of the simulations are shown in Figure 5, and the effect of the thermal bridges can be appreciated there. These thermal bridges make the power consumption of the freezer compartment greater, since some of this cooling power has to cool the thermoelectric compartment (super-conservation compartment). On the other hand, a lower electric power consumption of the Peltier modules is needed. As a consequence of this, the power consumption of the refrigerator decreases, since less heat flux from the hot side of the Peltier modules is introduced into the refrigerator. The most important value is the total power consumption of the hybrid refrigerator (the addition of the electric power consumption of the freezer, thermoelectric and refrigerator compartments) and this value decreases if thermal bridges are used. This effect is greater as the size of the thermal bridges is bigger. After these results, we decided to build a new hybrid prototype with two thermal bridges, each of them 200*200*10mm.

Results of the different prototypes of hybrid refrigerators.

During the development of this work and based on the data from the simulations, three different hybrid refrigerators have been built.

The temperatures of the first prototype are shown in Figure 4 and in Table 2, where they are compared with the temperature values predicted by the computational model. These results certify that the first prototype works properly, keeping the thermoelectric compartment at 0ºC, even if the room temperature rises to 30ºC. The power consumption for an ambient temperature of 25ºC is: 0.67kWh per day (28W) for the refrigerator, 0.58kWh per day (24.1W) for the freezer and 0.2kWh per day (9W) for the thermoelectric cooling system, what means a total power consumption of 1.5kWh per day (61W).

In Figure 6, there are two pictures of the construction process of the third prototype of hybrid refrigerator. Two thermal bridges of 200*200*10mm were incorporated, based on the results provided by the computational model (see Figure 5). Table 4 shows a resume of the results obtained from the tests run on prototype 3 for steady state. It can be seen that these results match with the computational results (see Figure 5), which foresee a decrease in the power consumption of the Peltier modules and in the total electric power consumption. If these results are compared with prototype 1 results

(see Table 2), it can be checked that the total electric power consumption of the hybrid refrigerator, for a ambient temperature of 25ºC, has decreased from 60.3W to 49.9W, what means an improvement of 20%, due to the thermal bridges. Another important conclusion obtained from the data in Table 4 is that, when the thermostat of the refrigerator compartment is in a lower position, the total power consumption decreases. This is due to the fact that when the thermostat is in lower temperature positions, the temperature in the refrigerator is lower, what makes the Peltier modules work with a greater value of COP and, thus, lower power consumption. This fact makes, in addition, that the Peltier modules introduce less heat flux into the refrigerator.

This effect is greater than the effect of lowering the temperature by a lower position of the thermostat, so that the total power consumption is lower.

To conclude, a domestic refrigerator has been developed with a new super-conservation compartment, based on thermoelectricity, where the temperature is kept constant at 0ºC.

The total power consumption of the appliance is highly competitive. For example, for an ambient temperature of 25ºC, the power consumption of the refrigerator compartment is For an ambient temperature of 30 ºC, the temperature of the thermoelectric compartment can be kept constant at 0 ºC, as can be seen in figures 4 and 7. Obviously, if the ambient temperature rose, the electric power consumption would increase. In particular, if the ambient temperature rises from 25ºC to 30ºC, the electric power consumption is increased by 30%, as can be seen in table 4.

CONCLUSIONS

A new computational model that uses the numerical method of finite differences has been developed. This model is capable of simulating whole hybrid refrigerator (refrigerator compartment, freezer compartment and thermoelectric compartment). The model has been experimentally validated. It predicts the temperature in the thermoelectric compartment with a maximum error of 1.2ºC, and the electric power consumption with a relative error of 8%.

A thermoelectric system has been designed for the super-conservation compartment. It has been placed in a domestic refrigerator, which uses vapor compression as cooling system. The temperature of the super-conservation compartment is kept constant at 0ºC, even if the ambient temperature rises to 30ºC. This design has been optimized with a thermal bridges system, which implies an additional heat flux from the thermoelectric compartment to the freezer, reducing the total power consumption by 20%.

To conclude, we developed a three-compartments-hybrid refrigerator, whose total power consumption is very competitive. For an ambient temperature of 25ºC, the electric power consumptions were:

-Refrigerator compartment compressor (T average = 4ºC): 0. Since this application has a big commercial interest, it has been patented under [10].

The company that is using this patent is Bosch-Siemens.

[10] J.G. Vián, D.

Figure 1 .

 1 Figure 1. Sketches of the hybrid domestic refrigerator. Configurations I and II.

  and 3 the discretization of both configurations are shown. The electrothermal analogy has been used.

Figure 2 .

 2 Figure 2. Sketch of the discretization of the hybrid refrigerator for configuration I.

Figure 3 .

 3 Figure 3. Sketch of the discretization of the hybrid refrigerator for configuration II.

Figure 4 .

 4 Figure 4. Comparison of the results from the prototype and the computational model.

Figure 5 .

 5 Figure 5. Results of the simulations for the refrigerator with thermal bridges.

Figure 7 .

 7 Figure 7. Results of the prototype 3 with a supplied voltage for the Peltier modules of 2.9V

  19.7W, the freezer compartment consumes 25.2W and the thermoelectric device 3.1W, what makes a total power consumption of 48.1W. According to European rules on energy efficiency of refrigerators, this new model could be included on class B.

  47 kWh/day (19.7W) -Thermoelectric modules (T average = 0ºC): 0.07 kWh/day (3.1W) -Freezer compartment compressor (T average = -21ºC): 0.6 kWh/day (25.2W) -Total power consumption of the hybrid refrigerator: 1.15kWh/day (48.1W) According to European rules on energy efficiency of refrigerators, this developed model could be included on class B.

Table 1 .

 1 Dimensions of the hybrid refrigerator

		COMPARTMENTS
		Refrigerator compartment	Freezer Compartment	Thermoelectric Compartment
	Height (m)	0.750	0.618	0.317
	Width (m)	0.458	0.470	0.405
	Length (m)	0.460	0.400	0.405
	Inner Volume (m 3 )	0,1580	0,1162	0,0520
		WALL THICKNESSES
		Refrigerator compartment	Freezer Compartment	Thermoelectric Compartment
	Lateral walls (m)	0.060	0.070	0.070
	Rear wall (m)	0.065	0.070	0.075
	Ceiling wall (m)	0.060	0.062	0.053
	Bottom wall (m)	0.053	0.106	0.062
	Front door (m)	0.060	0.080	0.080

Table 2 .

 2 Resume of the results for the first prototype and the computational model for steady state.

	INPUTS			OUTPUTS
				TEMPERATURES		ELECTRIC POWER CONSUMPTION
	Ta	Vte		Tref	Tte	Tcong	Pref	Pcong	Pte	Ptotal
	(ºC)	(V)		(ºC)	(ºC)	(ºC)	(W)	(W)	(W)	(W)
	25	3.6	Experimental data	6,1	0,6	-23,1	27,3	24,1	8,9	60,3
	25	3.6	Computational data	6,09	-0,52	-23,11	28,9	26,1	8,7	63,8
	25	3.6	Deviation	0 ºC	1,2 ºC	0,0ºC	6,1%	8,3%	1,9%	5,8%
	30	4	Experimental data	6,0	1,1	-23,5	35,0	28,9	11,2	75,2
	30	4	Computational data	6,01	-0,08	-23,38	35,8	30,2	10,7	76,7
	30	4	Deviation	0ºC	1,2ºC	-0,1ºC	2,1%	4,5%	4,6%	2,1%

Table 3 .

 3 Results of the simulations for the studied configurations.

	CONFIGURATION I

Table 4 .

 4 Prototype 3 results for steady state.

		DATA					RESULTS
				TEMPERATURES	POWER CONSUMPTION
	Ta	Thermostat	Vte	Tref	Tte	Tcong	Pref	Pcong	Pte	Ptotal
	(ºC)	position	(V)	(ºC)	(ºC)	(ºC)	(W)	(W)	(W)	(W)
	25	6 ºC	2,2	5,5	-0,3	-22,1	19,7	25,2	4,9	49,9
	30	6 ºC	2,9	6,1	0,0	-22,1	26,9	30,9	7,4	65,2
	30	4 ºC	2,3	4,6	0,1	-22,8	26,1	30,4	5,3	61,9

Hybrid refrigerator with thermal bridges

Peltier module

Thermoelectric modules assembly

Fin dissipater