Axillary dissection in patients with preoperative positive nodal cytology: Genuine need or overtreatment?

Recent studies demonstrated the possibility to avoid axillary dissection (ALND) in selected patients with one or two metastatic nodes. Otherwise, patients with positive nodal ultrasound-guided fine-needle aspiration cytology (US-FNAC) currently undergo ALDN. The aim of this study is to quantify the nodal burden in patients with positive US-FNAC treated with ALND and to evaluate if clinical or pathological characteristics associated with low nodal involvement can be identified. This is a multicentric retrospective study involving 297 patients who underwent ALND because of a positive preoperative US-FNAC. A total of 157 patients showed bulky axillary lymph nodes at diagnosis, and 70% of them had three or more metastatic nodes. One hundred and forty patients had a clinically negative axilla and in 50% of them, 4 or more metastatic nodes were found with axillary dissection. Overall, the median number of metastatic nodes was 5. Favorable pathological characteristics of tumors were found in patients with only one or two metastatic nodes: smaller primary tumor, a lower proportion of grade 3, invasive lobular carcinomas and a higher proportion of low-Ki67 tumors. In the group of patients with clinically negative axilla and potentially meeting ACOSOG Z0011 criteria, 22 (31%) showed less than three metastatic axillary nodes. A preoperative positive axillary FNAC is associated with a metastatic nodal burden significantly higher than in patients with positive sentinel lymph node biopsy (SLNB). Nevertheless, about 30% of patients with cN0 axilla, positive axillary FNAC performed because of suspicious nodes on imaging, T1-2 primary tumor and breast-conserving surgery showed less than three metastatic axillary nodes, thus meeting ACOSOG Z0011 trial's criteria and therefore would be eligible for skipping ALND according to current guidelines

BRCA Mutation Status in Triple-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: A Pivotal Role for Treatment Decision-Making

Simple Summary In this retrospective observational study, we evaluated data from patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT) in order to better define the impact of germline BRCA1/2 (gBRCA1/2) mutation status on outcomes in this patient population. Our results show that patients with BRCA1/2 mutation had a higher pathologic complete response (pCR) rate than non-mutated patients; nevertheless, the benefit was confirmed only in the subset of patients who received a platinum-based NACT. Furthermore, pCR was associated with improved Event Free Survival (EFS) and Overall Survival (OS), regardless of BRCA1/2 mutation status and type of NACT received. Long-term follow-up analyses are needed to further define the impact of gBRCA mutation status in patients with early-TNBC. Triple-negative breast cancer (TNBC) is characterized by earlier recurrence and shorter survival compared with other types of breast cancer. Moreover, approximately 15 to 25% of all TNBC patients harbor germline BRCA (gBRCA) 1/2 mutations, which confer a more aggressive phenotype. However, TNBC seems to be particularly sensitive to chemotherapy, the so-called 'triple negative paradox'. Therefore, Neoadjuvant chemotherapy (NACT) is currently considered the preferred approach for early-stage TNBC. BRCA status has also been studied as a predictive biomarker of response to platinum compounds. Although several randomized trials investigated the addition of carboplatin to standard NACT in early-stage TNBC, the role of BRCA status remains unclear. In this retrospective analysis, we evaluated data from 136 consecutive patients with Stage I-III TNBC who received standard NACT with or without the addition of carboplatin, in order to define clinical features and outcomes in BRCA 1/2 mutation carriers and non-carrier controls. Between January 2013 and February 2021, 67 (51.3%) out of 136 patients received a standard anthracyclines/taxane regimen and 69 (50.7%) patients received a platinum-containing chemotherapy regimen. Deleterious germline BRCA1 or BRCA2 mutations were identified in 39 (28.7%) patients. Overall, patients with deleterious gBRCA1/2 mutation have significantly higher pCR rate than non-carrier patients (23 [59%] of 39 vs. 33 [34%] of 97; p = 0.008). The benefit of harboring a gBRCA mutation was confirmed only in the subset of patients who received a platinum-based NACT (17 [65.4%] of 26 vs. 13 [30.2%] of 43; p = 0.005) while no differences were found in the platinum-free subgroup. Patients who achieved pCR after NACT had significantly better EFS (OR 4.5; 95% CI 1.9-10.7; p = 0.001) and OS (OR 3.3; 95% CI 1.3-8.9; p = 0.01) than patients who did not, regardless of BRCA1/2 mutation status and type of NACT received. Our results based on real-world evidence show that TNBC patients with the gBRCA1/2 mutation who received platinum-based NACT have a higher pCR rate than non-carrier patients, supporting the use of this chemotherapy regimen in this patient population. Long-term follow-up analyses are needed to further define the role of gBRCA mutation status on clinical outcomes in patients with early-TNBC

A Systems Biology Approach to Characterize the Regulatory Networks Leading to Trabectedin Resistance in an In Vitro Model of Myxoid Liposarcoma

Trabectedin, a new antitumor compound originally derived from a marine tunicate, is clinically effective in soft tissue sarcoma. The drug has shown a high selectivity for myxoid liposarcoma, characterized by the translocation t(12;16)(q13; p11) leading to the expression of FUS-CHOP fusion gene. Trabectedin appears to act interfering with mechanisms of transcription regulation. In particular, the transactivating activity of FUS-CHOP was found to be impaired by trabectedin treatment. Even after prolonged response resistance occurs and thus it is important to elucidate the mechanisms of resistance to trabectedin. To this end we developed and characterized a myxoid liposarcoma cell line resistant to trabectedin (402-91/ET), obtained by exposing the parental 402-91 cell line to stepwise increases in drug concentration. The aim of this study was to compare mRNAs, miRNAs and proteins profiles of 402-91 and 402-91/ET cells through a systems biology approach. We identified 3,083 genes, 47 miRNAs and 336 proteins differentially expressed between 402-91 and 402-91/ET cell lines. Interestingly three miRNAs among those differentially expressed, miR-130a, miR-21 and miR-7, harbored CHOP binding sites in their promoter region. We used computational approaches to integrate the three regulatory layers and to generate a molecular map describing the altered circuits in sensitive and resistant cell lines. By combining transcriptomic and proteomic data, we reconstructed two different networks, i.e. apoptosis and cell cycle regulation, that could play a key role in modulating trabectedin resistance. This approach highlights the central role of genes such as CCDN1, RB1, E2F4, TNF, CDKN1C and ABL1 in both pre- and post-transcriptional regulatory network. The validation of these results in in vivo models might be clinically relevant to stratify myxoid liposarcoma patients with different sensitivity to trabectedin treatment

Let-7a-5p, miR-100-5p, miR-101-3p, and miR-199a-3p Hyperexpression as Potential Predictive Biomarkers in Early Breast Cancer Patients

Background: The aim of this study is to identify miRNAs able to predict the outcomes in breast cancer patients after neoadjuvant chemotherapy (NAC). Patients and methods: We retrospectively analyzed 24 patients receiving NAC and not reaching pathologic complete response (pCR). miRNAs were analyzed using an Illumina Next-Generation-Sequencing (NGS) system. Results: Event-free survival (EFS) and overall survival (OS) were significantly higher in patients with up-regulation of let-7a-5p (EFS p = 0.006; OS p = 0.0001), mirR-100-5p (EFS s p = 0.01; OS p = 0.03), miR-101-3p (EFS p = 0.05; OS p = 0.01), and miR-199a-3p (EFS p = 0.02; OS p = 0.01) in post-NAC samples, independently from breast cancer subtypes. At multivariate analysis, only let-7a-5p was significantly associated with EFS (p = 0.009) and OS (p = 0.0008). Conclusion: Up-regulation of the above miRNAs could represent biomarkers in breast cancer

How Can CpG Methylations, and Pair-to-Pair Correlations between the Main (Gene) and the Opposite Strands, Suggest a Bending DNA Loop: Insights into the 5′-UTR of DAT1

A working hypothesis issues from patterns of methylation in the 5′-UTR of the DAT1 gene. We considered relationships between pairs of CpGs, of which one on the main-gene strand and another on the complementary opposite strand (COS). We elaborated on data from ADHD children: we calculated all possible combinations of probabilities (estimated by multiplying two raw values of methylation) in pairs of CpGs from either strand. We analyzed all correlations between any given pair and all other pairs. For pairs correlating with M6-M6COS, some pairs had cytosines positioning to the reciprocal right (e.g., M3-M2COS and M6-M5COS), other pairs had cytosines positioning to the reciprocal left (e.g., M2-M3COS; M5-M6COS). Significant pair-to-pair correlations emerged between main-strand and COS CpG pairs. Through graphic representations, we hypothesized that DNA folded to looping conformations: the C1GG C2GG C3GG and C5G C6G motifs would become close enough to allow cytosines 1-2-3 to interact with cytosines 5-6 (on both strands). Data further suggest a sliding, with left- and right-ward oscillations of DNA strands. While thorough empirical verification is needed, we hypothesize simultaneous methylation of main-strand and COS DNA (“methylation dynamics”) to serve as a promising biomarker

γ-secretase is differentially modulated by alterations of Homocysteine cycle in neuroblastoma and glioblastoma cells.

Multiple aspects of homocysteine metabolism were studied to understand the mechanism responsible for hyperhomocysteinemia toxicity in Alzheimer disease. Besides oxidative stress and vascular damage, homocysteine has also a great importance in regulating DNA methylation through S-adenosylmethionine, the main methyl donor in eukaryotes. Alterations of S-adenosylmethionine and methylation were evidenced in Alzheimer disease and in elderly. In order to clarify whether DNA methylation can provide the basis for amyloid-β overproduction, we used human SK-N-BE neuroblastoma and A172 glioblastoma cell lines. We tested the effects of folate, B12 and B6 deprivation and S-adenosylmethionine addition on methylation metabolism. Our results indicate that homocysteine accumulation induced through vitamin B deprivation could impair the "Methylation Potential" with consequent presenilin 1, BACE and amyloid-β upregulation. Moreover, we found that homocysteine alterations had an effect on neuroblastoma but not on glioblastoma cells; this suggests a possible differential role of the two cell types in Alzheimer disease. © 2007 - IOS Press and the authors. All rights reserved

A study of the aphasics expressive process under the jungian psychological focus

This article describes a exploratory research that applies a plastic expressive technique in expression aphasics, victims of ischemic stroke in the left hemisphere. Objetive: Investigates the intervention results through case studies based on the clinical method and qualitative analysis, with the theoretical focus on jungian psychology. Method: It uses tests before and after the intervention, such as external criterion. The projective thechnique House-Tree-Person - HTP, shows consonant results with the ones observed on expressive process; the emotional perception test International Affective Picture System - IAPS and its response record system Self-Assessment Manikin - SAM, enables to launch hypothesis on the emotional transformation of participants; the European Brain Injury Questionnaire - EBIQ, offers substratum to discuss the transformation of the subjects own vision of their problems. Through the Collective Subject Discourse method, identifies stages of the expressive process with contents common to the group. Results: The results of the case studies, the DSC and assessment tools reveal that, in the end, the participants, without exception, were strengthened, closer to their own reality and enriched in touch with themselves and with the outside world. Conclusion: Assessment tools to confirm by ticking the therapeutic value of the proposed technique and suggesting that this form of intervention may be helpful in the process of rehabilitation of aphasic.Este artigo descreve uma pesquisa exploratória em que se aplica técnica expressiva plástica a afásicos de expressão, vítimas de acidente vascular cerebral isquêmico (AVCI) no hemisfério esquerdo. Objetivo: Investigar os resultados da intervenção realizando estudos de caso com base no método clínico e análise qualitativa, com enfoque teórico da psicologia junguiana. Método: Utiliza testes antes e depois da intervenção, como critério externo: a técnica projetiva HTP - House-Tree-Person, aponta mudanças de personalidade condizentes com as observadas no processo; o teste de percepção emocional International Affective Picture System - IAPS, e seu sistema de registro de respostas Self-Assessment Manikin - SAM, auxilia a lançar hipóteses sobre a transformação emocional dos participantes; o European Brain Injury Questionnaire - EBIQ, fornece substratos para discutir a transformação da visão dos sujeitos sobre seus próprios problemas. Mediante o método do Discurso do Sujeito Coletivo identifica etapas do processo expressivo com conteúdos comuns ao grupo atendido. Resultados: Os resultados dos estudos de caso, do DSC e dos instrumentos de avaliação revelam que, ao final, os participantes, sem exceção, mostraram-se fortalecidos, mais próximos da sua própria realidade e enriquecidos no contato consigo mesmos e com o mundo externo. Conclusão: Os instrumentos de avaliação o confirmam, assinalando o valor terapêutico da técnica proposta e sugerindo que esta forma de intervenção pode ser útil no processo de reabilitação de afásicos

Um estudo do processo expressivo de afásicos sob enfoque da psicologia junguiana

Este artigo descreve uma pesquisa exploratória em que se aplica técnica expressiva plástica a afásicos de expressão, vítimas de acidente vascular cerebral isquêmico (AVCI) no hemisfério esquerdo. Objetivo: Investigar os resultados da intervenção realizando estudos de caso com base no método clínico e análise qualitativa, com enfoque teórico da psicologia junguiana. Método: Utiliza testes antes e depois da intervenção, como critério externo: a técnica projetiva HTP - House-Tree-Person, aponta mudanças de personalidade condizentes com as observadas no processo; o teste de percepção emocional International Affective Picture System - IAPS, e seu sistema de registro de respostas Self-Assessment Manikin - SAM, auxilia a lançar hipóteses sobre a transformação emocional dos participantes; o European Brain Injury Questionnaire - EBIQ, fornece substratos para discutir a transformação da visão dos sujeitos sobre seus próprios problemas. Mediante o método do Discurso do Sujeito Coletivo identifica etapas do processo expressivo com conteúdos comuns ao grupo atendido. Resultados: Os resultados dos estudos de caso, do DSC e dos instrumentos de avaliação revelam que, ao final, os participantes, sem exceção, mostraram-se fortalecidos, mais próximos da sua própria realidade e enriquecidos no contato consigo mesmos e com o mundo externo. Conclusão: Os instrumentos de avaliação o confirmam, assinalando o valor terapêutico da técnica proposta e sugerindo que esta forma de intervenção pode ser útil no processo de reabilitação de afásicos.This article describes a exploratory research that applies a plastic expressive technique in expression aphasics, victims of ischemic stroke in the left hemisphere. Objetive: Investigates the intervention results through case studies based on the clinical method and qualitative analysis, with the theoretical focus on jungian psychology. Method: It uses tests before and after the intervention, such as external criterion. The projective thechnique House-Tree-Person - HTP, shows consonant results with the ones observed on expressive process; the emotional perception test International Affective Picture System - IAPS and its response record system Self-Assessment Manikin - SAM, enables to launch hypothesis on the emotional transformation of participants; the European Brain Injury Questionnaire - EBIQ, offers substratum to discuss the transformation of the subjects own vision of their problems. Through the Collective Subject Discourse method, identifies stages of the expressive process with contents common to the group. Results: The results of the case studies, the DSC and assessment tools reveal that, in the end, the participants, without exception, were strengthened, closer to their own reality and enriched in touch with themselves and with the outside world. Conclusion: Assessment tools to confirm by ticking the therapeutic value of the proposed technique and suggesting that this form of intervention may be helpful in the process of rehabilitation of aphasic

Urokinase expression in course of benign and malignant mammary lesions: comparison between nodular and healthy tissues

Purpose: Increased expression of urokinase (uPA), a member of the serine protease family, is an effector of metastatic cascade and has been reported in various malignancies, including breast cancer. uPA overexpression in cancer tissues was correlated with a more aggressive phenotype and it is considered a strong and independent unfavorable prognostic factor in breast cancer. Methods: Using real-time PCR assay, we analyzed uPA expression of malignant and benign breast nodular lesions versus healthy tissues (normal breast and lymphocytes). Results: We found that besides breast cancer nodule, normal mammary gland and lymphocytes overexpressed uPA too. Tissues obtained from women with benign lesions expressed homogeneous and lower uPA. Conclusions: In conclusion, although uPA overexpression is typical of cancer tissues, it could be considered as a feature of the whole organism affected by cancer. On the basis of these first results, uPA could be considered for further studies as a possible useful therapeutic target in breast cancer. © 2009 Springer-Verlag