NDRG4 promoter hypermethylation is a mechanistic biomarker associated with metastatic progression in breast cancer patients.

The risk of developing metastatic disease in breast cancer patients is traditionally predictable based on the number of positive axillary lymph nodes, complemented with additional clinicopathological factors. However, since lymph node-negative patients have a 20-30% probability of developing metastatic disease, lymph node information alone is insufficient to accurately assess individual risk. Molecular approaches, such as multigene expression panels, analyze a set of cancer-related genes that more accurately predict the early risk of metastasis and the treatment response. Here, we present N-Myc downstream-regulated gene 4 (NDRG4) epigenetic silencing as a mechanistic biomarker of metastasis in ductal invasive breast tumors. While aberrant NDRG4 DNA hypermethylation is significantly associated with the development of metastatic disease, downregulation of NDRG4 transcription and protein expression is functionally associated with enhanced lymph node adhesion and cell mobility. Here, we show that epigenetic silencing of NDRG4 modulates integrin signaling by assembling ß1-integrins into large punctate clusters at the leading edge of tumor cells to promote an "adhesive switch," decreasing cell adhesion to fibronectin and increasing cell adhesion and migration towards vitronectin, an important component of human lymph nodes. Taken together, our functional and clinical observations suggest that NDRG4 is a potential mechanistic biomarker in breast cancer that is functionally associated with metastatic disease.

Surgical anatomy of the internal thoracic lymph nodes in fresh human cadavers: basis for sentinel node biopsy.

BACKGROUND: While the optimal management of early breast cancer patients with sentinel lymph node (SLN) involvement mapped in the internal thoracic chain is still debated, biopsy may be performed when surgeons select patients who are most likely to benefit. The aim of this study is to examine anatomical aspects of internal thoracic nodes (ITNs) to orientate SLN biopsy in the parasternal area. METHODS: This study was based on dissections of 29 female cadavers. The parameters analyzed were the number of intercostal spaces (ICSs) containing at least one ITN, mean number of nodes in each ICS, position of the ITNs in relation to the internal thoracic artery (ITA), number of retrocostal spaces (RCSs) containing at least one ITN, and mean number of nodes in each RCS. RESULTS: The ICS that was most likely to have at least one ITN was the third, with 86.2% in the right side and 75.8% in the left side. In the second ICS, the rates were 69.2 and 73.6%, and in the fourth, the rates were 48.1 and 33.3%. In the third ICS, on both sides, the mean number of ITNs was the highest (1.2). A tendency of the nodes to be laterally located in the second ICS and medially located in the downward dissection was observed. Most of the RCSs did not present any nodes. CONCLUSIONS: This study indicates that most of the second and third ICSs presented at least one ITN, and the mean number of nodes in the third space was greater. There is a tendency to find nodes medial to the artery downwards from the second to the fourth ICS. ITNs are generally located in ICSs, and the majority of RCSs did not contain any nodes.

Magnetic resonance imaging-guided occult breast lesion localization and simultaneous sentinel lymph node mapping.

BACKGROUND: Radio-guided occult lesion localization is a valid technique for the diagnosis of suspicious non-palpable lesions. Here we determine the feasibility of pre-operative localization of occult suspect non-palpable breast lesions using radio-guided occult lesion localization, as well as for identifying the sentinel lymph node. METHODS: This is a descriptive study of data collected retrospectively. Pre-operative mapping of 34 breast lesions in 25 patients suspected of being malignant was performed using conventional imaging methods with a magnetic resonance imaging-guided radiopharmaceutical injection. RESULTS: The mean time required to perform the localization was 25 minutes. After resection of the lesions using a gamma probe, malignancy was confirmed in fifteen patients (60.0%), with nine invasive ductal carcinomas, two invasive lobular carcinomas, and four in situ ductal carcinomas The resection was confirmed by the complete removal of the radioactive material. The pathologic results and images were concordant in all but two cases, which were submitted for new magnetic resonance imaging examinations and surgery that confirmed the malignancies. Of the 15 patients with confirmed malignancies, 10 had sentinel lymph node resection. Of these, eight were negative for metastases, one had micro-metastases and one had confirmed metastases. Three patients had full axillary node dissection, with metastases found in only one. No side effects were observed with magnetic resonance-guided radiopharmaceutical injection. CONCLUSIONS: The sentinel node occult lesion localization technique is a simple, reproducible and effective alternative approach to occult lesions compared to other methods, such as mammotomy and the hook-wire localization technique, for mapping suspect breast lesions and identifying lymph node metastasis.

Intraoperative full-dose of partial breast irradiation with electrons delivered by standard linear accelerators for early breast cancer.

Purpose. To assess feasibility, efficacy, toxicity, and cosmetic results of intraoperative radiotherapy (IORT) with electrons delivered by standard linear accelerators (Linacs) during breast conserving surgeries for early infiltrating breast cancer (BC) treatment. Materials and Methods. A total of 152 patients with invasive ductal carcinoma (T ≤ 3.0 cm) at low risk for local relapses were treated. All had unicentric lesions by imaging methods and negative sentinel node. After a wide local excision, 21 Gy were delivered on the parenchyma target volume with electron beams. Local recurrences (LR), survival, toxicity, and cosmetic outcomes were analyzed. Results. The median age was 58.3 years (range 40-85); median follow-up was 50.7 months (range 12-101.5). There were 5 cases with LR, 2 cases with distant metastases, and 2 cases with deaths related to BC. The cumulative incidence rates of LR, distant metastases, and BC death were 3.2%, 1.5%, and 1.5%, respectively. Complications were rare, and the cosmetic results were excellent or good in most of the patients. Conclusions. IORT with electrons delivered by standard Linacs is feasible, efficient, and well tolerated and seems to be beneficial for selected patients with early infiltrating BC.

Radicality effect of adding an interpectoral to a subpectoral approach for dissection of level III axillary lymph nodes in breast cancer.

AIMS AND BACKGROUND: The extent of axillary lymph node dissection for breast cancer treatment is tailored to each patient. When the surgeon assumes that full dissection, including level III, is needed, there are basically two ways for reaching the apical nodes while preserving the pectoralis muscles: a subpectoral approach, below the joined pectoralis muscles, and another that includes an additional interpectoral dissection between the muscles. We conducted a study to evaluate the radicality of dissection using these two approaches. METHODS: To determine whether the harvest of level III axillary lymph nodes is equivalent with the different approaches, we prospectively studied 75 patients with breast cancer. Careful axillary lymph node dissection was done to as radical an extent as possible, first below the lateral edge of the joined pectoralis muscles (subpectoral approach) and sequentially after opening the space between the muscles (additional interpectoral approach). The number of patients with extra level III nodes retrieved by the addition of an interpectoral dissection as well as the number of complementary nodes obtained in such patients were determined. RESULTS: We excised 1701 axillary lymph nodes in 75 patients (mean, 22.7). Using first the subpectoral approach, we resected 259 level III nodes in 68 patients (mean, 3.8); in 56 patients, we removed 132 additional level III nodes using the supplementary interpectoral approach (mean, 2.4). In 7 patients (9.3%), we found at least one metastatic node with the interpectoral approach. Two of these patients had positive level III nodes that were discovered only by addition of the interpectoral dissection. CONCLUSIONS: The dissection of level III axillary nodes is more radical when an additional interpectoral dissection is performed after a subpectoral approach has been used. The exclusive subpectoral approach frequently leaves residual nodes at the apex of the axilla.

Quimioterapia neoadjuvante com o esquema TAC em câncer de mama localmente avançado: apresentação e discussão de nove casos / Neoadjuvant chemotherapy with TAC schedule in locally advanced breast cancer: presentation and discussion of nine cases

São apresentados e discutidos, em confronto com dados encontrados na literatura, os resultados de nove casos de câncer de mama localmente avançado e que receberam quimioterapia neoadjuvante com o esquema de quimioterapia TAC (docetaxel, doxorrubicina e ciclofosfamida).

The authors showed the results of nine cases of locally advanced breast cancer treated with the chemotherapy schedule TAC (docetaxel, doxorubicin and cyclophosphamide) and discussed the literature.

Avaliação da espiritualidade no enfrentamento do câncer de mama / Assessiment of spirituality in breast cancer

O diagnóstico de câncer de mama é um evento muito estressante para pacientes e suas famílias. No Brasil, a estimativa de incidência para o ano de 2006 foi de aproximadamente 49 mil novos casos. O câncer de mama e seu subseqüente tratamento têm impacto significativo no funcionamento físico, mental e bem-estar da mulher. Algumas mulheres têm encontrado em sua espiritualidade ajuda no enfrentamento das crises físicas e psicológicas causadas pelo diagnóstico e tratamento. Neste estudo trnasversal, 30 mulheres atendidadas em um hospital público, um particular e em um grupo de auxílio a pacientes com câncer, participaram respondendo à Escala de Coping Religioso-Espiritual (CRE). Para a análise dos resultados, utilizaram-se os parâmetros da Escala CRE e a Análise de Variância de Kruskal Wallis. Pela análise dos valores médios de CRE Total, a freqüência de uso da espiritualidade foi de 2,51 a 3,50, considerada média para 20,0% das mulheres, de 3,51 a 4,50 alta para 76,7% e altíssima, de 4,51 a 5,00, para 3,3% das mulheres. Não houve diferença significante na utilização da espiritualidade, quando comparadas em relação a renda, religião, grau de instrução e estado civil. Os achados sugerem a importância da espiritualidade para mulheres com câncer de mama.

The diagnosis of breast cancer is a very stressful event for patients and their families. In Brazil, the estimate of incidence for the year 2006 was approximately 49,000 new cases. The breast cancer and its subsequent treatment have significant impact in physical functioning, mental and well-being of the woman. Some women have found in their spirituality support in the coping of physical and psychological crisis caused by the diagnosis and treatment. In this transversal study, thirty women assisted in a public hospital, an private and a group of aid to patients with cancer had participated responding the Religious-Spiritual Coping (SRCOPE) Scale. For analysis of the results, the parameters of SRCOPE Scale and Kruskal Wallis Analysis of Variance have been used. By analysis of the average values of Total SRCOPE, the frequency of use of the spirituality was from 2.51 to 3.50, considered average for 20.0% of the women, from 3.51 to 4.50 high for 76.7% and the highest, from 4.51 to 5.00 to 3.3% of women. There was no significant difference in use of spirituality, according to religion, revenue, education, and marital status. The findings suggest the importance of spirituality for coping in women with breast cancer.

História natural do câncer de mama / Natural history of the breast cancer

Ao que tudo indica, a lesão genética iniciadora do câncer de mama ocorre em tecidos precursores da neoplasia. Formando-se o tumor, seu ritmo de crescimento é determinado basicamente pela função de proliferação celular, com desenvolvimento lento. A principal via de disseminação das células neoplásicas da mama é linfática e, após os êmbolos neoplásicos atingirem a circulação sistêmica, podem ser neutralizados pelo sistema de defesa do hospedeiro (resposta imune inata ou adaptativa) ou se multiplicar a distãncia. As assinaturas genéticas de cada tumor relacionam-se com o seu potencial metastatizante e a predileção por certos órgãos-alvo.

Apparently, the genetic lesion initiator of breast cancer occurs in tissues precursors of neoplasia. Forming the tumor, its growth rate is basically determined by the function of cell proliferation, with slow development. The major route of spread of breast cancer cells is lymphatic and after neoplastic emboli reach the systemic circulation, can be neutralized by the system of host defense (innate or adaptive immune response) or multiply the distance. Genetic signatures of each tumor are related to their potential metastasizing and the preference for certain target organs.

Avaliação da amplitude de movimentação do ombro homolateral à biópsia de linfonodo sentinela axilar / Shoulder movement extent evaluation after axiliary sentinel lymph node biopsy

É bem sabido que a dissecção axilar total para tratamento do câncer de mama leva a mais complicações motoras e sensitivas para o braço do lado operado do que a simples biópsia de linfonodo sentinela (BLS). No entanto, não está estabelecido se o aparecimento tratado por BLS também apresenta limitações. Este estudo foi realizado com a intenção de avaliar a amplitude de movimentação (ADM) do ombro de mulheres operadas de quadrantectomia mamária e BLS, comparando as avaliações pré e pós operatórias (depois de 1,2 e 3 meses). Foram analisadas 38 pacientes cuja a mensuração da ADM foi feita por goniometria. Os parâmetros motores do ombro analisados foram: flexão, extensão, abdução, adução, rotação interna e rotação externa. Foram considerados resultados pós-operatórios anormais aqueles com restrição motora superior a 10 graus. Alterações significativas de flexão e abdução do ombro foram notadas em todos os casos no primeiro mês (100%), diminuíram no segundo (86,4% e 76,3%, respectivamente) e desapareceram no terceiro. Os demais parâmetros de ADM não se alteraram com a BLS. A evolução da média dos valores encontrados para cada parâmetro é apresentada na forma de gráficos. Em conclusão, existe naturalmente sem intervenção fisioterapêutica limitação de ADM do ombro após BLS, mas ela persiste apenas nos primeiros dois meses e compromete apenas funções de flexão e abdução. Por isso, cuidados fisioterapêuticos precoces devem ser recomendados mesmo após BLS.

It is well known that full axillary dissection for breast cancer patients treatment causes sensitive and motor alterations in the homolateral upper limb more frequently than sentinel node biopsy (SNB). Nevertheless it is not clear if a patient treated by SNB presents those alterations as well. This research was done aiming to evaluate the shoulder movement extent (SME) evaluation in women who underwent to mammary quadrantectomy and SNB pre and post-operatively (after 1, 2 and 4 months). A total of 38 patients were analysed by means of goniometry, focusing the following motor parameters: flexion, extension, abduction, aduction, internal retation and external rotation. Abnormal post-operative results were considered when motor restriction were greater than 10 degrees. Significative alterations in shouder flexion and abduction were observed in all patients (100%) during the first month, diminishing in the second month (86,4% and 76,3% of the patients respectively) and always disappearing in the third month. The other shoulder movement parameters have not altered. The mean values of each of the parameters are presented in graphics. It was concluded that without physiotherapeutic intervention, some SME restriction occurs after SNB, lasts about 2 months and is related to flexion and abduction parameters. So early post-operative physiotherapeutic care should be recommended also for breast cancer patients treated by SNB.

Genética, biologia molecular e carcinogênese mamária / Genetics, molecular biology and mammary carcinogenesis

Neste artigo são apresentados conceitos atuais sobre a carcinogênese mamária, enfocando aspectos de genética e de biologia molecular. Sabe-se que a carcinogênese pode ser subdividida em três fases: iniciação, promoção e progressão. A iniciação decorre de lesão genética em uma única célula-tronco, quase sempre localizada em lóbulo indiferenciado (tipo I). A alteração genética fundamental é a inativação de genes supressores (esporádica ou hereditária) ou a ativação de proto-oncogenes. A promoção é basicamente hormonal, destacando-se o papel dos esteróides sexuais, que atuam mediante interação com proteínas receptoras intranucleares. Na fase de progressão, ocorre a invasão da membrana basal e do estroma e embolização linfática, após perda no processo de adesão entre as células em conseqüência de ação de enzimas proteolíticas.

Current concepts on mammary carcinogenesis focusing genetics and molecular biology are presented. The carcinogenic process can be divided in 3 phases: initiation, promotion and progression. Initiation occurs in only one stem cell located in undifferentiated lobules (type I) and is caused by a genetic damage. The main genetic alteration is suppressor gene inactivation (sporadic or hereditary) or proto-oncogene activation. Promotion is basically due to steroid hormones action which interacts with intra-nuclear receptor proteins. After loosing adhesion malignant cells produce proteolytic enzymes, invade basal membrane and stroma and can embolyze through lymphatic channels.

A sexualidade das pacientes submetidas à mastectomia radical / The sexuality of patients submitted to radical mastectomy

O diagnóstico e o tratamento do câncer de mama promovem alterações na vida da mulher, entre elas, as relacionadas à vivência de sua sexualidade. Avaliar a presença de problemas ligados à sexualidade em pacientes submetidas a mastectomia radical. Este trabalho é um estudo piloto de outro com um número maior de pacientes. Foram avaliadas as alterações da sexualidade em pacientes submetidas a mastectomia radical com (n = 10) e sem reconstrução (n = 9), com três meses de pós-cirúrgico, utilizando o Watts Sexual Function Questionnaire, um questionário norte-americano que avalia os quatro componentes da experiência sexual - incluindo as percepções sobre desejo sexual, interesse, orgasmo e satisfação -, específico para mensurar a sexualidade em sujeitos com patologias clínicas. A este questionário foram acrescidas questões objetivando a avaliação e a observação das reações das pacientes frente ao diagnóstico cirúrgico e às possíveis alterações advindas da mastectomia radical na auto-estima, no humor, na capacidade de planejar o futuro e na manutenção do relacionamento afetivo-sexual. Os resultados preliminares mostraram que as pacientes submetidas a mastectomia radical sem reconstrução apresentam indícios positivos de disfunções sexuais (anorgasmia) quando comparadas ao grupo que fez reconstrução. Indícios da presença de depressão foram observados em 31,57% da amostra. Destas pacientes, duas (uma em cada grupo) verbalizaram intenção suicida durante a aplicação do questionário. Há indícios de comprometimento da sexualidade em pacientes submetidas a mastectomia radical sem reconstrução, quando comparadas àquelas submetidas a mastectomia radical com reconstrução, no que concerne à presença de disfunção orgásmica.

The diagnosis and treatment for breast cancer promotes changes in women's life, and beside this, those related with her sexual life. Evaluate the presence of sexual problems related to the sexuality of women submitted to radical mastectomy. Methods: this work has a pilot character of a study with a larger number of patients. They were evaluated changes of the sexuality in patients submitted to the radical mastectomy patients with reconstruction (n = 10) and to the radical mastectomy patients without reconstruction (n = 10), at three months after the surgery, using Watts Sexual Function Questionnaire, an American questionnaire which assesses four components of sexual experience which includes perceptions of sexual desire, arousal, orgasm and satisfaction, specific to evaluate sexuality in people with clinic pathologies. To this questionnaire were added aiming ate the evaluation and observation of the reactions of the patients in front of the surgical diagnosis and the possible alterations resulted of the radical mastectomy in self-esteem, in the humor, in the capacity to plan the future and in maintenance of the affectionate-sexual relationship. The results of this investigation are preliminary, regarding a pilot sample and they showed that the patients submitted to radical mastectomy without reconstruction positive presents indication of sexual dysfunction, mainly in what it concerns to orgasmic function (orgasmic dysfunction), when compared with the group with reconstruction. Indications of the depression presence were observed in 31,57% of the sample. Of these patients, two (one in each group) related suicidal intention during the questionnaire application. There is indication sexuality compromising in patients submitted to the radical mastectomy without reconstruction when compared to those underwent to radical mastectomy with reconstruction, in what concerns to the presence of orgasmic dysfunction.

Terapia de reposição hormonal e a mama / Hormonal replacement theraphy and the breast

A terapia de reposição hormonal (TRH) tem sido muito usada para alívio de sintomas climatéricos. Porém, como se sabe, os hormônios esteróides, principalmente os estrogênios, exercem ação promotora na carcinogênese mamária, a segurança da TRH em termos de risco de câncer de mama pode ser questionada. Nesta revisão de literatura, os autores concluíram que a TRH eleva discretamente o risco relativo de câncer de mama, podendo ser considerada quando as vantagens superarem as desvantagens. Mas, para mulheres com antecedente pessoal de câncer de mama ou com fatores predisponentes de alto risco, a TRH deve ser evitada, preferindo-se alternativas não-hormonais.

Hormonal replacement therapy (HRT) has been widely used for the 1llanagement of climateric symptoms. As it is known that steroid hormones, mainly estrogens, are promoting factors for mammary carcinogenesis, the safety of HRT in terms of risk for breast cancer may be cause of concern. In this review literature the authors concluded that HRT increases slightly the relative risk of breast cancer, and may by tailoring considered when the advantages exceed the disadvantages. Neverthless HRT should be avoided in women with personal history of breast cancer or presenting high risk predisposing factors, to whom non-hormonal alternatives are preferred.

Avaliação da morbidade e funcionalidade do membro superior em mulheres submetidas à linfadenectomia axilar total e biópsia de linfonodo sentinela por câncer de mama / Evaluation of the arm morbidity and function in women who underwent axillary lymph node dissection or sentinel lymph node biopsy for breast cancer treatment

Objetivos: avaliar e comparar a incidência de linfedema, dor, restrição de movimento e déficit sensorial no membro superior, após linfanedectomia axilar total (LAT) e biópsia de linfinodo sentinala (BLS) para tratamento de câncer de mama. Método: neste estudo incluíram-se pacientes que realizaram ressecção segmentar de mama e LAT ou BLS. O grupo A (n=100) formado por casos submetidos à LAT e o grupo B, por casos submetidos à BLS (n=50). As pacientes foram analisadas por meio de questionário, no qual foram incluídos sintomas de linfedema, dor, restrição da amplitude de movimento e déficit sensorial após o procedimento cirúrgico. A avaliação fisioterapêutica foi realizada pela perimetria e goniometria de membros superiores. Resultado: no grupo A houve diferenças significativas (p<0,05) em todos os sintomas avaliados, existindo maior queixa de edema (31 por cento), dor (58 por cento), restrição do movimento (52 por cento) e dormência (57 por cento). No grupo B houve menor prevalência da sensação de edema (2 por cento), dor (26 por cento), restrição do movimento (24 por cento) e dormência (20 por cento), em todos os tempos estudados.

Localização radioguiada de lesões mamárias não-palpáveis, exame anatomopatológico e biópsia de linfonodo sentinela no mesmo ato operatório / Radioguided localization of non-palpable breast lesions, intraoperative anatomopathological analysis and sentinel lymph node biopsy at the same surgery

O objetivo deste estudo foi apresentar uma nova estratégia para o manejo de lesões mamárias suspeitas de malignidade, a qual combina a localização radioguiada (ROLL), mapeamento de linfonodo sentinela (LS), exame de congelação e, se necessário, ressecção segmentar da mama e biópsia linfonodal. Foram estudados 115 casos (101 lesões mamárias não-palpáveis suspeitas de malignidade e 14 cânceres não-palpáveis descobertos por mamotomia prévia). Na véspera da cirurgia foi injetada no centro da lesão (ou na área do clipe pós-mamotomia) uma solução contendo 0,2 ml de dextram e 15 MBq de 99mTc, por orientação ultrasonográfica ou estereotáxica. No dia seguinte, todas as pacientes foram submetidas à biópsia cirúrgica orientada por probe detector de radiação gama, radiografia da peça cirúrgica e exame de congelação. A taxa de confirmação de remoção das lesões foi de 100 por cento, sendo que o LS foi mapeado por linfacintilografia em 97,4 por cento (112/115). O exame anatomopatológico intra-operatório revelou 29 carcinomas infiltrativos, 13 carcinomas ductais in situ, 11 hiperplasias atípicas, 42 alterações fibrocísticas e 6 resultados inconclusivos. Na comparação com os resultados verificados no exame definitivo ou parafina notaram-se 3 (2,9 por cento) resultados falsos-negativos e nenhum falso-positivo. O LS foi imediatamente biopsiado 50 casos de malignidade, dos quais 3 estiveram comprometidos pelo exame citológico na hora e mereceram dissecção axilar completa. Em conclusão, ROLL e biópsia de LS podem ser empregados simultaneamente mediante uma injeção única de 99mTc ligada a dextram. Esta técnica possibilita exame de congelação, cirurgia conservadora, biópsia de LS e dissecção axilar total se necessário.

Induction of experimental mammary carcinogenesis in rats with 7,12-dimethylbenz(a)anthracene.

PURPOSE: To test an experimental model of chemical mammary carcinogenesis induction in rats. METHODS: Twenty young virgin Sprague-Dawley female rats, aged 47 days, received 20 mg of 7,12-dimethylbenz(a)anthracene (DMBA) intragastrically by gavage. Afterwards, at 8 and 13 weeks, their mammary glands were examined. At the end of the experiment, the animals were sacrificed, and the mammary tumors were measured and weighed. Tumor fragments were analyzed using light microscopy. RESULTS: Eight weeks after DMBA injection, 16 rats presented at least 1 breast tumor (80%). After 13 weeks, all of them (100%) developed breast carcinomas that were confirmed by histopathological analysis. CONCLUSION: This experimental animal model of chemical mammary induced carcinogenesis is feasible and can be used in further experiments on the role of tumorigenic biomodulator substances.