It is widely accepted that breast milk is the optimal source of infant nutrition. Despite the World Health Organization (WHO) recommendation of exclusive breastfeeding for the first 6 months of infant life, many women discontinue breastfeeding as a result of perceived difficulties. Nipple pain is a highly prevalent, significant reason for breastfeeding cessation. Among the numerous interventions for nipple pain, the application of lanolin is commonly recommended, with endorsement by Health Canada, The La Leche League, and International Board Certified Lactation Consultants. The few studies that have evaluated the effectiveness of lanolin on nipple pain have lacked methodologic rigor, and are thus not reliable or generalizable. As such, the purpose of this trial was to rigourously evaluate the effect of lanolin for the treatment of nipple pain among breastfeeding women. This single-site randomized controlled trial (RCT) compared the application of lanolin (treatment) to usual postpartum care (not applying lanolin) for the treatment of nipple pain. The primary outcome for this trial was the effect on pain severity, as measured by a numeric rating scale (NRS) at 4 days post-randomization. Of 186 participants, 93 were randomized to the treatment group and 93 to the usual care group. At 4 and 7 days post-randomization there were no statistically significant differences in pain scores between groups. It is noteworthy that by 7 days post-randomization there were clinically relevant decreases in nipple pain in both groups. However, there were no statistically significant differences between groups for other outcomes, including pain measured with the short-form McGill Pain Questionnaire, breastfeeding duration, breastfeeding exclusivity, and breastfeeding self-efficacy. Despite these findings, women in the treatment group were significantly more satisfied receiving lanolin for their nipple pain than those receiving usual care. Since the use of lanolin is no more effective than applying nothing to the nipples for the management of nipple pain, the widespread use of lanolin is questionable. Further research is required on the role of interventions to prevent nipple pain and damage, and the effect of anticipatory guidance on improving breastfeeding outcomes for those experiencing nipple pain in the early postpartum period.

Yes / Purpose: Nipple secretions are protein-rich and a potential source of breast cancer biomarkers for breast cancer screening. Previous studies of specific proteins have shown limited correlation with clinicopatholigical features. Our aim, in this pilot study, was to investigate the intra- and inter-patient protein composition of nipple secretions and the implications for their use as liquid biopsies. Experimental design: Matched pairs of NAF (n=15) were characterised for physicochemical properties and SDS PAGE. Four pairs were selected for semi-quantitative proteomic profiling and trypsin-digested peptides analysed using 2D LC Orbitrap Fusion mass spectrometry. The resulting data was subject to bioinformatics analysis and statistical evaluation for functional significance. Results: A total of 1990 unique proteins were identified many of which are established cancer associated markers. Matched pairs shared the greatest similarity (average Pearson correlation coefficient of 0.94), but significant variations between individuals was observed. Conclusions: This was the most complete proteomic study of NAF to date providing a valuable source for biomarker discovery. The high level of milk proteins in healthy volunteer samples compared to the cancer patients was associated with galactorrhoea. Using matched pairs increased confidence in patient-specific protein levels but changes relating to cancer stage require investigation of a larger cohort. / Proteomics research was supported by Yorkshire Cancer Research projects, BPP047 and B381PA.

Yes / There has been tremendous progress in detection of breast cancer in postmenopausal women, resulting in two-thirds of women surviving more than 20 years after treatment. However, breast cancer remains the leading cause of cancerrelated deaths in premenopausal women. Breast cancer is increasing in younger women due to changes in life-style as well as those at high risk as carriers of mutations in high-penetrance genes. Premenopausal women with breast cancer are more likely to be diagnosed with aggressive tumours and therefore have a lower survival rate. Mammography plays an important role in detecting breast cancer in postmenopausal women, but is considerably less sensitive in younger women. Imaging techniques, such as contrast-enhanced MRI improve sensitivity, but as with all imaging approaches, cannot differentiate between benign and malignant growths. Hence, current well-established detection methods are falling short of providing adequate safety, convenience, sensitivity and specificity for premenopausal women on a global level, necessitating the exploration of new methods. In order to detect and prevent the disease in high risk women as early as possible, methods that require more frequent monitoring need to be developed. The emergence of “omics” strategies over the last 20 years, enabling the characterisation and understanding of breast cancer at the molecular level, are providing the potential for long term, longitudinal monitoring of the disease. Tissue and serum biomarkers for breast cancer stratification, diagnosis and predictive outcome have emerged, but have not successfully translated into clinical screening for early detection of the disease. The use of breast-specific liquid biopsies, such as nipple aspirate fluid (NAF), a natural secretion produced by breast epithelial cells, can be collected non-invasively for biomarker profiling. As we move towards an age of active surveillance, home-based liquid biopsy collection kits are increasingly being applied and these could provide a paradigm shift where NAF biomarker profiling is used for routine breast health monitoring. The current status of established and newly emerging imaging techniques for early detection of breast cancer and the potential for alternative biomarker screening of liquid biopsies, particularly those applied to high-risk, premenopausal women, will be reviewed. / Proteomics research was supported by Yorkshire Cancer Research projects, BPP047 and B381PA, and co-funded by the European Regional Development Fund and the Republic of Cyprus through the Research Promotion Foundation projects ΥΓΕΙΑ/ΒΙΟΣ/0311(ΒΙΕ/07) and NEKYP/0311/17.

Submitted by Ricardo Cedraz Duque Moliterno (ricardo.moliterno@uefs.br) on 2017-03-16T22:28:22Z No. of bitstreams: 1 Disserta??o Jana?na Vers?o final_02-06.pdf: 687363 bytes, checksum: d808a60f7664fc60a1270e67fa83601a (MD5) / Made available in DSpace on 2017-03-16T22:28:22Z (GMT). No. of bitstreams: 1 Disserta??o Jana?na Vers?o final_02-06.pdf: 687363 bytes, checksum: d808a60f7664fc60a1270e67fa83601a (MD5) Previous issue date: 2015-05-07 / This study aimed to assess factors associated with nipple trauma in women who breastfeed, resulting in two articles. The first entitled "Factors associated with nipple trauma in lactation period: a systematic review" was based on the search of publications indexed in the databases Medical Literature Analysis and Retrieval System Online/Pubmed, Latin American and Caribbean Health Sciences, and ScienceDirect, with no restriction on language or publication period. As risk factors for nipple trauma were identified: mother with white or yellow race/color, primiparity, cracked nipples in previous pregnancies, mother who does not live with a partner, use of anesthesia in parturition, gestational age of the newborn between 37 to 40 weeks, presence of breastfeeding in the first hour of life, semi protrude and/or malformed nipples, malposition between mother and child, incorrect lacth of the infant in mother's breast, presence of breast engorgement, nipple pain, use of nursing bottle, use of pacifier and lactational mastitis. On the other hand, the guidance received about how to lacth and positioning the infant in the maternal breast during prenatal was considered as a protective factor against the nipple trauma. The second article entitled "Nipple fissure: study of latent variables in the first month postpartum" consisted of a cross-sectional analysis of a birth cohort, an observational and prospective character, who studied the mother-child dyad. The prevalence of cracked nipples observed in mothers who breastfeed in the first month postpartum was 35.9%. It was found among the latent variables that the unfavorable maternal emotional state (OR= 1.65; 95% CI= 1.26-2.16) and lower availability for breastfeeding (OR= 1.80; 95% CI= 1.25-2.59) were associated with cracked nipples, as well as the covariates parturition in unit that is not recognized as a Baby Friendly Hospital (OR= 1.48; 95% CI= 1.07-2.03), cesarean section (OR= 1.72; 95% CI= 1.33-2.24) inadequate positioning of the newborn during breastfeeding (OR= 3.91; 95% CI= 1.02-14.99), incorrect lacth of the infant the in the maternal breast (OR= 14.36; 95% CI= 7.80-26.46) and the presence of breast engorgement (OR= 2.74; 95% CI= 2.10-3.58). Preventive measures against the risk factors of nipple trauma are necessary to prevent this important cause of pain during breastfeeding and premature weaning. / Este estudo teve como objetivo avaliar os fatores associados ao trauma mamilar em lactantes, tendo como resultado dois artigos. O primeiro intitulado ?Fatores associados ao trauma mamilar no per?odo lactacional: uma revis?o sistem?tica? foi fundamentado na busca de publica??es indexadas nas bases de dados Medical Literature Analysis and Retrieval System Online/Pubmed, Literatura Latino-Americana e do Caribe em Ci?ncias da Sa?de, e ScienceDirect, sem restri??o de idioma ou per?odo de publica??o. Foram identificados como fatores de risco para o trauma mamilar: m?e de ra?a/cor branca ou amarela, primiparidade, presen?a de fissura mamilar em gesta??es anteriores, m?e n?o residir com o companheiro, uso de anestesia no parto, idade gestacional do rec?m-nascido entre 37e 40 semanas, presen?a de mamada na primeira hora de vida, mamilos semiprotrusos e/ou mal formados, posicionamento inadequado entre m?e e filho, pega incorreta do lactente ao seio materno, presen?a de ingurgitamento mam?rio, dor mamilar, uso de mamadeira, uso de chupeta e mastite lactacional. Por outro lado, a orienta??o recebida sobre pega e posicionamento do lactente ao seio materno durante o pr?-natal foi considerada como fator de prote??o contra o trauma mamilar. O segundo artigo intitulado ?Fissura mamilar: estudo de vari?veis latentes no primeiro m?s p?s-parto? consistiu em uma an?lise transversal de uma coorte de nascidos vivos, de car?ter observacional e prospectiva, que estudou a d?ade m?e-filho. A preval?ncia de fissura mamilar observada em lactantes no primeiro m?s p?s-parto foi de 35.9%. Verificou-se entre as vari?veis latentes que o estado emocional materno desfavor?vel (OR= 1.65; IC 95%= 1.26-2.16) e menor disponibilidade para amamentar (OR= 1.80; IC 95%= 1.25-2.59) associaram-se ? fissura mamilar, assim como as covari?veis parto em unidade n?o credenciada como Hospital Amigo da Crian?a (OR= 1.48; IC 95%= 1.07-2.03), parto ces?reo (OR= 1.72; IC 95%= 1.33-2.24), posicionamento inadequado do neonato durante a mamada (OR= 3.91; IC 95%= 1.02-14.99), pega incorreta do lactente ao seio materno (OR= 14.36; IC 95%= 7.80-26.46) e presen?a de ingurgitamento mam?rio (OR= 2.74; IC 95%= 2.10-3.58). A??es de preven??o contra os fatores de risco do trauma mamilar s?o necess?rias para evitar esta importante causa de dor durante a mamada e de desmame precoce.

The heterogeneity of breast cancer (disease stage and phenotype) makes it challenging to differentiate between each subtype; luminal A, luminal B, HER2, basal-like and claudin-low, on the basis of a single gene or protein. Therefore, a collection of markers is required that can serve as a signature for diagnosing different types of breast cancer. New developments in proteomics have provided the opportunity to look at phenotype-specific breast cancer cell lines and stage-specific liquid biopsies (nipple aspirate fluid [NAF], plasma samples) to identify disease and phenotype specific signature. An 8-plex iTRAQ quantification strategy was employed to compare proteomic profiles of a range of breast cancer and ‘normal-like’ cell lines with primary breast epithelial cells. From this, 2467 proteins were identified on Orbitrap Fusion and Ultraflex II, of which 1430 were common. Matched pairs of NAF samples from four patients with different stages of breast cancer, were analysed by SCX-LC-MS and a total of 1990 unique gene products were identified. More than double the number of proteins previously published data, were detected in NAF, including 300 not detected in plasma. The NAF from the diseased patients have 138 potential phenotype biomarkers that were significantly changed compared to the healthy volunteer (7 for luminal A, 9 for luminal B, 11 for HER2, 14 for basal-like and 52 for claudin-low type). The average coefficient of variation for triplicate analyses by multiple reaction monitoring mass spectrometry (MRM-MS), was 9% in cell lines, 17 % in tissue biopsies, 22% in serum samples and 24% in NAF samples. Overall, the results provide a strong paradigm to develop a clinical assay based on proteomic changes in NAF samples for the early detection of breast cancer supplementary to established mammography programmes.

Lactogenesis II is critical stage of lactation and it is hindered by conditions like caesarean section, premature delivery, obesity, age, and parity. Previous studies have shown a connection between morphological characteristics of breast and nipple-areola complex and lactation onset. Higher number of areolar glands and their non-uniform distribution has been linked to earlier onset of lactation. Extremely large breasts and short nipples has been linked to breastfeeding difficulty. Aim of this study was to investigate relationship between morphological characteristics of breast and nipple-areola complex (number and distribution of areolar glands, nipple, areola, and breast area, protrusion of nipple and areola, and contrast of breast and areola) and lactation onset. For this purpose, we collected breasts and areolae photographs of 141 mothers one day postpartum in maternity ward in Prague and compared the morphological traits to lactogenesis II onset. We have found a non-uniform distribution of areolar glands with the highest abundance on upper lateral quadrant of areola. We found that right breast area tends to be bigger than left, and left nipple and areola tends to be longer than right. Parity had significant effect on lactation onset. No morphological characteristics have been linked to...

The CD-ROM disc containing supplementary material is kept in the cardboard box in the Systems Office. / The heterogeneity of breast cancer (disease stage and phenotype) makes it challenging to differentiate between each subtype; luminal A, luminal B, HER2, basal-like and claudin-low, on the basis of a single gene or protein. Therefore, a collection of markers is required that can serve as a signature for diagnosing different types of breast cancer. New developments in proteomics have provided the opportunity to look at phenotype-specific breast cancer cell lines and stage-specific liquid biopsies (nipple aspirate fluid [NAF], plasma samples) to identify disease and phenotype specific signature. An 8-plex iTRAQ quantification strategy was employed to compare proteomic profiles of a range of breast cancer and ‘normal-like’ cell lines with primary breast epithelial cells. From this, 2467 proteins were identified on Orbitrap Fusion and Ultraflex II, of which 1430 were common. Matched pairs of NAF samples from four patients with different stages of breast cancer, were analysed by SCX-LC-MS and a total of 1990 unique gene products were identified. More than double the number of proteins previously published data, were detected in NAF, including 300 not detected in plasma. The NAF from the diseased patients have 138 potential phenotype biomarkers that were significantly changed compared to the healthy volunteer (7 for luminal A, 9 for luminal B, 11 for HER2, 14 for basal-like and 52 for claudin-low type). The average coefficient of variation for triplicate analyses by multiple reaction monitoring mass spectrometry (MRM-MS), was 9% in cell lines, 17 % in tissue biopsies, 22% in serum samples and 24% in NAF samples. Overall, the results provide a strong paradigm to develop a clinical assay based on proteomic changes in NAF samples for the early detection of breast cancer supplementary to established mammography programmes. / The supplementary material submitted with the thesis is not available online.

Early detection of breast cancer is critical for increasing survival rates. However, currently available screening strategies provide ambiguous results, leaving invasive tissue biopsy procedures necessary for definitive diagnosis. Considerable efforts have investigated using nipple aspirate fluid (NAF), a liquid biopsy rich in proteins representative of the breast microenvironment, as a non-invasive source of early detection biomarkers. However, by using traditional two-dimensional discovery proteomic approaches, many technical challenges of using NAF have limited analysis of large sample sizing: such as low expressed volume (<10µL) or insufficient analytical material (<200µg protein). Following non-invasive collection by manual massage, we developed a one-dimensional sample preparation workflow that reduced sample handling steps, minimised sample losses and increased sample throughput to 96-samples by using a PVDF-membrane based system, which was ideally suited to the NAF proteome. Samples were prepared within a single working day, and results correlated significantly with conventional in-solution protocols. ​Proteins typically associated with the dysregulation of innate immune response and haemostatic pathways had a significantly altered proteome profile in response to breast cancer. Overall, our new workflow will allow future studies to take a more high-throughput approach, revealing biomarkers for breast cancer early detection, and providing a real impact.

O constante aumento do número de novos casos de câncer de mama vem despertando interesse na elaboração de módulos de esquemas CAD a fim de proporcionar um diagnóstico de maior precisão. Entretanto, a maioria das pesquisas está empenhada em detectar ou classificar fatores primários presentes em imagens mamográficas, como módulos e microcalcificações. Áreas assimétricas, retração de mamilo, linfonodos axilares, entre outros, são considerados como fatores secundários no diagnóstico do câncer de mama, apesar de poderem alertar para o surgimento não só dessa, mas de outras doenças no futuro. Por isso, essa pesquisa contempla a implementação de um sistema computacional capaz de auxiliar na detecção e classificação, conforme padrão BI-RADS®, de regiões que contenham sinais secundários capazes de levantar suspeitas da presença ou surgimento do câncer de mama, em imagens mamográficas digitais, utilizando técnicas inteligentes e automáticas de processamento de imagens e redes neurais artificiais. A acurácia alcançada em cada etapa foi: detecção de assimetria de 82,8%, retração de mamilo de 95% e Az = 0,93, detecção de linfonodos axilares = 74,9%. Objetiva-se que o resultado do trabalho seja inserido como um dos módulos de um protótipo de esquema CADx em mamografia, a fim de ampliar o conjunto de informações a serem usadas na classificação de cada caso sob análise, visando o aumento da precisão diagnóstica. / The increase in the number of cases of breast cancer have attracted interest in developing modules of CAD schemes to provider higher diagnostic accuracy. However, most researches are engaged in detect and classify primary factors present in mammographic images such as nodules and microcalcifications. Asymmetric areas, nipple retraction, axilary limph nodes, among other, are considered as secondary factors to diagnostic the breast cancer, although they may alert for the emergence not only of this but of other diseases in the future. Thus, this research includes the implementation of a computer system able to assist in the detection and classification, according to BI-RADS®, of regions that containing secondary signals able to arousing suspicion of the presence or appearance of breast cancer in digital mammographic images using intelligent and automatic techniques in the image processing and artificial neural networks. The accuracy obtained in each step was: detection of asymmetry of 82.8%, nipple retraction of 95% and Az = 0.93, detection of axilary lymph nodes = 74.9%. The purpose is that the result of the work is entered as one of the modules of a prototype of CADx schem in mammography in order to extend the range of information to be used in the classification of each case under analysis, aiming to increase diagnostic accuracy.

O constante aumento do número de novos casos de câncer de mama vem despertando interesse na elaboração de módulos de esquemas CAD a fim de proporcionar um diagnóstico de maior precisão. Entretanto, a maioria das pesquisas está empenhada em detectar ou classificar fatores primários presentes em imagens mamográficas, como módulos e microcalcificações. Áreas assimétricas, retração de mamilo, linfonodos axilares, entre outros, são considerados como fatores secundários no diagnóstico do câncer de mama, apesar de poderem alertar para o surgimento não só dessa, mas de outras doenças no futuro. Por isso, essa pesquisa contempla a implementação de um sistema computacional capaz de auxiliar na detecção e classificação, conforme padrão BI-RADS®, de regiões que contenham sinais secundários capazes de levantar suspeitas da presença ou surgimento do câncer de mama, em imagens mamográficas digitais, utilizando técnicas inteligentes e automáticas de processamento de imagens e redes neurais artificiais. A acurácia alcançada em cada etapa foi: detecção de assimetria de 82,8%, retração de mamilo de 95% e Az = 0,93, detecção de linfonodos axilares = 74,9%. Objetiva-se que o resultado do trabalho seja inserido como um dos módulos de um protótipo de esquema CADx em mamografia, a fim de ampliar o conjunto de informações a serem usadas na classificação de cada caso sob análise, visando o aumento da precisão diagnóstica. / The increase in the number of cases of breast cancer have attracted interest in developing modules of CAD schemes to provider higher diagnostic accuracy. However, most researches are engaged in detect and classify primary factors present in mammographic images such as nodules and microcalcifications. Asymmetric areas, nipple retraction, axilary limph nodes, among other, are considered as secondary factors to diagnostic the breast cancer, although they may alert for the emergence not only of this but of other diseases in the future. Thus, this research includes the implementation of a computer system able to assist in the detection and classification, according to BI-RADS®, of regions that containing secondary signals able to arousing suspicion of the presence or appearance of breast cancer in digital mammographic images using intelligent and automatic techniques in the image processing and artificial neural networks. The accuracy obtained in each step was: detection of asymmetry of 82.8%, nipple retraction of 95% and Az = 0.93, detection of axilary lymph nodes = 74.9%. The purpose is that the result of the work is entered as one of the modules of a prototype of CADx schem in mammography in order to extend the range of information to be used in the classification of each case under analysis, aiming to increase diagnostic accuracy.