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Treatment with Tucatinib in addition to Pertuzumab and Trastuzumab in patients with HER2-positive metastatic breast cancer (HER2+ MBC) after local therapy of isolated brain progression: InTTercePT, a UCBG/GINECO study. Background HER2+ MBC patient on first line treatment with pertuzumab and trastuzumab have a 13% risk of developing brain metastasis (BM) as the first site of progression. For such patient with isolated brain progression, guidelines recommend to use central nervous system (CNS) directed therapy whenever possible (stereotactic radiosurgery or surgery or both). These patients will have a higher risk of subsequent brain and systemic progression after local treatment. Therefore, whether systemic treatment should be continued or changed remains an open question. The tyrosine kinase inhibitor tucatinib is an orally bioavailable HER2 inhibitor with validated antineoplastic activity and the ability to cross the blood brain barrier. The randomized HER2CLIMB study, demonstrated that adding tucatinib to trastuzumab/capecitabine improved both progression-free survival (PFS) and overall survival (OS) among HER2+ MBC patients previously treated with trastuzumab, pertuzumab and T-DM1. Particularly, this regimen demonstrated improved antitumor activity in patients with BM, in terms of CNS-PFS and OS. Exploratory analysis of HER2CLIMB and in a phase 1b study, showed patients who continued systemic treatment with tucatinib (in combination either with trastuzumab/capecitabine or TDM-1) after CNS-directed treatment had a better outcome compared with those that discontinued systemic tucatinib-based treatment. These results suggest that for patient in the first line metastatic setting who experience isolated brain progression, adding tucatinib to the trastuzumab/pertuzumab regimen could help control BM, improve PFS, OS and patients’ quality of life. Trial design InTTercePT is an open-label, single-arm, national, multicentric, phase II trial assessing the combination of tucatinib, pertuzumab and trastuzumab. Tucatinib will be administered orally twice daily at 300 mg. Pertuzumab and trastuzumab will be administered at the initial dose of 840 mg and 8 mg/kg respectively following by a maintenance dose of 420 mg and 6mg/kg respectively, 3-weekly. If indicated, hormone therapy is allowed in combination with HER2-directed therapy. Eligibility criteria include HER2+ MBC with isolated brain progression (new or progressive BM with stable or responding systemic disease) under pertuzumab/trastuzumab treatment (± taxane) after complete local treatment (surgery and/or radiation therapy). There is no limit to the number and size of BM. Specific aims To evaluate the efficacy, in terms of PFS rate (RECIST v1.1) of tucatinib in combination with pertuzumab/trastuzumab. Secondary endpoints include OS, brain PFS (RECIST v1.1) and BM response in patient not in complete remission at the brain level after local treatment and safety (NCI-CTCAE v5.0). Statistical methods Given the lack of safety data from this association, two interim safety analysis are planned: after 10 and 20 patients having received at least one dose of the treatments combination during at least one cycle. The number of patients to be included was calculated using Fleming’s single-stage procedure for phase II trials. The sample size calculation was based on a minimum success (non-progression rate at 6 months) considered of interest of p1 = 75% and an uninteresting rate of p0 = 60%. Assuming a unilateral type I error alpha of 10% and a power of 85%, 52 patients are needed. Considering 5% of the patients may be non-evaluable, 55 patients will be included. At the time of analysis, if at least 37 successes are observed, the treatment will be considered as interesting for further investigation. The study is recruiting. By July 1, 2022, 10 patients have been screened and 8 treated (NCT05041842). Funding SeaGen Contact information thomas.bachelot@lyon.unicancer.fr Citation Format: Thomas Bachelot, Christelle Jouannaud, Benjamin Verret, Sylvie Chabaud, Camille Petrau, Laetitia Stefani, Mony Ung, Isabelle Desmoulins, William Jacot, Caroline Bailleux, Sandrine Marques, Jérôme Lemonnier, Anne-Claire Hardy-Bessard. Treatment with Tucatinib in addition to Pertuzumab and Trastuzumab in patients with HER2-positive metastatic breast cancer (HER2+ MBC) after local therapy of isolated brain progression: InTTercePT, a UCBG/GINECO study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-10-01.

International audience; The clinical actionability of circulating tumor DNA requires sensitive detection methods with a short turnaround time. In the PADA-1 phase 3 trial (NCT03079011), metastatic breast cancer patients treated with an aromatase inhibitor and palbociclib were screened every 2 months for activating ESR1 mutations in blood (bESR1mut). We report the feasibility of the droplet digital polymerase chain reaction (ddPCR) and cross-validation with next-generation sequencing (NGS). bESR1mut testing was centralized in two platforms using the same ddPCR assay. Results were reported as copies/mL of plasma and mutant allele frequency (MAF). We analyzed 200 positive ddPCR samples with an NGS assay (0.5-1% sensitivity). Overall, 12,552 blood samples were collected from 1017 patients from 83 centers. Among the 12,525 available samples with ddPCR results, 11,533 (92%) were bESR1mut-negative. A total of 267 patients newly displayed bESR1mut (26% patients/2% samples) with a median copy number of 14/mL (range: 4-1225) and a median MAF of 0.83% (0.11-35), 648 samples (20% patients/5% samples) displayed persistent bESR1mut, and 77 (

Background: Mutations of ESR1 (ESR1mut), the gene encoding for Estrogen Receptor (ER) alpha, have been functionally characterized as driving resistance to aromatase inhibitors (AI) given to in ER+ HER2- metastatic breast cancer (mBC). In the randomized multicenter phase 3 PADA-1 trial (NCT03079011), ER+ HER2- mBC patients treated with first line AI+Palbociclib were screened every two months for ESR1mut in blood (bESR1mut), by subjecting cell-free circulating DNA (cfcDNA) to a droplet digital PCR (ddPCR) assay. Upon the onset of a rising (i.e., increasing or appearing) bESR1mut, patients with no concomitant disease progression were randomized between keeping the same regimen (AI-Palbociclib) or switching to Fulvestrant-Palbociclib. We report herein the sample flow of this first-in-its-class trial, from April 2017 to March 2021, and the cross-validation of ddPCR results with NGS. Methods: At each time point, 20 mL of blood were drawn into BCT Streck® tubes. cfcDNA was extracted from 4 mL of plasma. bESR1mut testing was centralized in 2 platforms using the same ddPCR assay, which combines a drop-off ddPCR, targeting the clustered hotspot L536, Y537 and D538 mutations found in exon 8, with an unconventional ddPCR interrogating specifically the E380Q mutation, located in exon 5 (Jeannot et al, Oncogene 2020). Results were expressed as the number of ESR1mut copies detected per mL of plasma together with the Mutant Allele Frequency (MAF). As a control, we submitted 200 ESR1mut+ (by ddPCR) left-over samples to an amplicon-based Next Generation Sequencing (NGS) assay covering all ESR1 exons - with a nominal sensitivity of >0.5% MAF. Results: From 03/2017 to 03/2021, 1,017 MBC patients have been included in 83 centers and 12,552 blood samples have been collected. The median time of delivery to central platforms was 1 day (range: [0-11]). A median volume of 9.5 mL [2-20] of plasma was obtained after 2 centrifugations. bESR1mut results were notified to investigators with a median turnaround time of 13 days [1-813] (32 days in 2017, 9 days in 2019, 8 days in 2021). Among the 12,525 available ddPCR results: N=77 ( Citation Format: Céline Callens, François-Clément Bidard, Anais Curto-Taribo, Olfa Trabelsi-Grati, Samia Melaabi, Suzette Delaloge, Anne-Claire Hardy-Bessard, Thomas Bachelot, Florian Clatot, Thibault De La Motte Rouge, Jean-Luc Canon, Laurent Arnould, Fabrice André, Sandrine Marques, Marc-Henri Stern, Jean-Yves Pierga, Anne-Vincent Salomon, Emmanuelle Jeannot, Frederique Berger, Ivan Bieche, Anne Pradines. Real time detection of ESR1 mutation in blood by droplet digital PCR in the PADA-1 trial: Feasibility and cross-validation with NGS [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-01.

Background: Aromatase inhibitors (AI) in combination with a CDK 4/6 inhibitor have been established as the standard first line treatment of non AI-resistant hormone receptor-positive (HR+) HER2- metastatic breast cancer (mBC) patients (pts). ESR1 mutations are known drivers of resistance to AIs in the metastatic setting but their actionability remains unknown. The phase 3 PADA-1 trial aimed both at refining the global safety of palbociclib combined to any AI as first line treatment of HR+ HER2- mBC pts, and at evaluating the clinical benefit associated with a switch to fulvestrant-palbociclib upon detection of a rising ESR1 mutation in blood (bESR1mut). Methods: PADA-1 (NCT03079011), a multicenter, randomized, open-label, phase 3 trial, enrolled HR+ HER2- mBC pts with no prior therapy for mBC, in the absence of AI-resistance. In the first step, pts received a combination of any AI and palbociclib at standard recommended doses and underwent centralized bESR1mut screening every two months. In the second step, bESR1mut+ pts with no clinical/imaging concomitant disease progression were randomized between continuing the same therapy (standard arm) or switching to fulvestrant-palbociclib (experimental arm). The third step consisted in an optional cross-over after tumor progression for patients randomized in the standard arm. PADA-1 co-primary endpoints were global safety of the combination of palbociclib + endocrine therapy in the whole population of patients, throughout the study, with focus on hematological toxicities; and PFS in the second step. We present here the results of the global safety co-primary endpoint. Results: From 3/2017 to 01/2019, 1017 pts were accrued in 83 sites. As per 05/2021, 272 pts were still in step 1, 35 in step 2, and 8 in step 3. The overall follow-up was 33.7 months. 232 pts have deceased. 333 SAEs have been reported, including 21 grade 5, 35 grade 4, 183 grade 3, 53 grade 2, 26 grade 1 and 15 unknown grade. Among the grade 5 cases, 2 have been declared as potentially related to the underlying treatment (Death of unknown cause, pulmonary embolism). No pt died of SARS-CoV2 infection. The main hematological toxicities encountered, as well as selected non-hematological events are described in Table 1. Permanent discontinuation of the treatment due to toxicity occurred in 39 pts/1017 (3.8%). Palbociclib dose decreases occurred in 419 (41.2%) pts. Conclusion: By the number of included patients, PADA-1 is the largest prospective trial with 1st line AI and palbociclib. Data confirm the favorable safety profile of palbociclib when combined to any AI +/- switch to fulvestrant. Hematological toxicity appears limited and is mostly restricted to non-clinically significant neutropenia. Permanent discontinuation was exceptional. Detailed per-step analyses will be presented. Table 1.Adverse events (% pts)Grade 3, N (%)Grade 4, N (%)Neutropenia628 (61.8%)83 (8.2%)Febrile neutropenia4 (0.4%)0Thrombocytopenia18 (1.8%)3 (0.3%)Anemia24 (2.4%)0Lymphocytopenia58 (5.7%)5 (0.5%)Insterstitial lung disease4 (0.4%)0Liver enzymes increase (AST/ALT)5 (0.5%)0Mucositis10 (1%)0 Citation Format: Suzette Delaloge, Anne-Claire Hardy-Bessard, Thomas Bachelot, Jean-Yves Pierga, Jean-Luc Canon, Florian Clatot, Fabrice André, Thibault De La Motte Rouge, Barbara Pistilli, Florence Dalenc, Nadine Dohollou, Olivier Arsene, Thierry Petit, Cecilia Riedl, François Morvan, Adina Marti, Emma Lachaier, Mihaela Achille, Michel Gozy, Anne Escande, Dominique Mille, Fanny Trouboul, Sandrine Marques, Jerome Lemonnier, Frederique Berger, François-Clément Bidard. First line aromatase inhibitor (AI) + palbociclib with randomized switch to fulvestrant + palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: Global safety results of PADA-1, a UCBG-GINECO phase III trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-16.

IntroductionThe combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) has recently become the gold standard for AI-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2−) advanced breast cancer. However, most patients receiving this combination will ultimately progress and require further therapies.Several studies have demonstrated that the onset of a ESR1 gene mutation lead to AIs resistance in the advanced setting. ESR1 mutations can be detected in circulating tumour DNA (ctDNA) using a digital PCR assay. Our study aims to prove the clinical efficacy of periodic monitoring for emerging or rise of ESR1 mutations in ctDNA to trigger an early change from AI plus palbociclib to fulvestrant plus palbociclib treatment while assessing global safety.MethodsPADA-1 is a randomised, open-label, multicentric, phase III trial conducted in patients receiving AI and palbociclib as first line therapy for metastatic ER +HER2- breast cancer. 1000 patients will be included and treated with palbociclib in combination with an AI. Patients will be screened for circulating blood ESR1 mutation detection at regular intervals. Patients for whom a rising circulating ESR1 mutation is detected without tumour progression (up to N=200) will be randomised (1:1) between (1) Arm A: no modification of therapy; and (2) Arm B: palbociclib in combination with fulvestrant, a selective ER down-regulator. At tumour progression, an optional crossover will be offered to patients randomised in arm A. The coprimary endpoints are (1) Grade ≥3 haematological toxicities and their associations with baseline characteristics and (2) progression-free survival in randomised patients.Ethics and disseminationThe study has been approved by the French medicines agency (ANSM) and by an ethics committee (ref 01/17_1 CPP Ouest-IV Nantes) in January 2017. The trial results will be published in academic conference presentations and international peer-reviewed journals.Trial registration numbersEudraCT: 2016-004360-18; NCT03079011.

Tese de mestrado, Bioquímica (Bioquímica Médica), Universidade de Lisboa, Faculdade de Ciências, 2019 Submitted by Cristina Manessiez (camanessiez@fc.ul.pt) on 2019-12-18T15:02:10Z No. of bitstreams: 1 ulfc125266_tm_Sandrine_Gordino.pdf: 5700026 bytes, checksum: 4c677d527384c12a9dfc7b362157f046 (MD5) Made available in DSpace on 2019-12-18T15:02:24Z (GMT). No. of bitstreams: 1 ulfc125266_tm_Sandrine_Gordino.pdf: 5700026 bytes, checksum: 4c677d527384c12a9dfc7b362157f046 (MD5) Previous issue date: 2019

1070 Background: In PADA-1 (NCT03079011), a phase III trial testing the clinical utility of ESR1mut detection, ER+ HER2- advanced breast patients (ABC pts) received Aromatase Inhibitor (AI) and Palbociclib (Pal) +/- LHRH agonist as first line therapy. PADA-1 was open to “AI-sensitive” pts, including those with de novo stage IV disease or metastatic relapse after adjuvant endocrine therapy but also pts with metastatic relapses during adjuvant tamoxifen (TAM). In this subsidiary analysis, we report the efficacy of AI+PAL as first line therapy in patients relapsing on adjuvant TAM. Methods: Main inclusion criteria in PADA-1 are: pre- or post-menopausal pts with ER+ HER2- ABC, who did not receive any prior therapy for ABC and who had no adjuvant AI or completed adjuvant AI for > 12 months or who had disease recurrence while on adjuvant TAM. Results: From 04/2017 to 01/2019, 1017 ABC pts have been included in PADA-1, of which 115 (11.3%) had a metastatic relapse while on adjuvant TAM (TAM only (N = 112) or TAM+GnRH agonist (N = 3)). Median age at inclusion was 46 years (range 25-81), and 58 (50.4%) patients had visceral disease. The median PFS under AI+PAL was 20.4 months (95%CI16.1;27.8) in patients relapsing during adjuvant TAM. In contrast, median PFS in patients with de novo metastatic disease and metastatic relapses after the completion of adjuvant endocrine therapy were 30.6 months (95%CI26.7;Not reached) and 27.8 months (95%CI24.1;30.)], respectively. A subgroup analysis among patients relapsing on adjuvant TAM showed that those relapsing during the first two years of adjuvant TAM had a shorter PFS (11.4 months 95%CI[8.7;20.7]) than those relapsing after 2 years of adjuvant TAM (23.8 months 95%CI[20.2;Not reached]). Conclusions: To our knowledge, these are the first data on first line AI+CDK4/6 inhibitor in patients relapsing on adjuvant TAM. While PFS on AI + PAL appears primarily driven by endocrine resistance status, our data show that AI+PAL is a valuable option also in patients relapsing during adjuvant TAM. Clinical trial information: NCT03079011 .

O presente relatório pretende apresentar um projeto de investigação-ação, realizado numa turma de 4.º ano do 1.º Ciclo do Ensino Básico, cujos objetivos basilares de investigação são compreender como podem atividades de educação intercultural nos primeiros anos de escolaridade contribuir para o desenvolvimento da competência comunicativa intercultural e compreender que conhecimentos, atitudes e capacidades os alunos desenvolvem a partir de projetos de interação com o Outro, em aula de inglês no 1.º CEB. Para atingir estes objetivos, propusemo-nos desenvolver a educação intercultural, tendo em conta as seguintes três dimensões: conhecimentos, atitudes e capacidades; através da realização de atividades adequadas a este nível de ensino e da implementação de um projeto eTwinning. O projeto eTwinning, intitulado Let’s get to know each other, contou com a participação de uma turma da Turquia, uma turma da Itália e uma turma da Guadalupe, envolvendo um universo total de oitenta e dois alunos, com idades compreendidas entre nove e onze anos de idade. Este projeto teve como intuito promover a interação entre crianças de diferentes nacionalidades, desenvolvendo um espírito de partilha, bem como a alteridade. A análise dos dados, recolhidos mediante o uso de instrumentos, como a videogravação das sessões, um inquérito por questionário, uma entrevista e inquéritos de avaliação, permitiu-nos concluir que a promoção da abordagem intercultural em aula de inglês no 1.º Ciclo de Ensino Básico desenvolve nos/as alunos/as um espírito de abertura ao Outro e à sua cultura, bem como o desejo de conhecer e interagir com o Outro. Concluímos, também, que o desenvolvimento da competência comunicativa intercultural nos primeiros anos de escolaridade semeia as bases de uma sociedade mais recetiva e equitativa, consciente de que se enriquece pela inclusão da diversidade This report is based on an action-research project, carried out on a group of children in 4th grade of Primary Education, in the English class, aiming: to understand how education activities for intercultural education in the first years of schooling contribute to the development of the intercultural communicative competence (ICC) and to understand what knowledge, attitudes and abilities the students develop from projects of interaction with the Other. In order to achieve these objectives, we have developed the intercultural education, by considering the following three dimensions: knowledge, attitudes and capacities, through activities appropriated to this level of education and the implementation of an eTwinning project. In the eTwinning project, entitled “Let's get to know each other”, participated classes from Turkey, Italy and Guadeloupe, involving a total universe of eighty-two students, aged nine to eleven. This project aimed to promote the interaction between children of different nationalities, developing a spirit of sharing, as well as alterity. The data analysis, collected through the use of instruments such as video recording, a questionnaire, an interview and assessment questionnaires, allowed us to conclude that the intercultural approach in the English class of Primary Education develops openness and respect to others and their culture, as well as the desire to know and interact with the Other. We also conclude that the development of intercultural communicative competence in the first years of schooling builds the foundations of a more receptive and equitable society, aware that it is enriched by the inclusion of diversity Mestrado em Ensino de Inglês no 1º Ciclo do Ensino Básico

Este estudo procura avaliar as competências de jovens graduados a trabalhar em empregos na área da Gestão de Recursos Humanos. Este apoia-se na autoavaliação de competências chave e de comunicação. Neste sentido, pretende identificar em que tipos de competências os jovens se sentem mais e menos preparados e quais são as principais fontes de aquisição dessas competências. A informação foi recolhida através de um inquérito de autoavaliação de competências que foi preenchido por jovens graduados a trabalhar ou estagiar na área de Gestão de Recursos Humanos (n=170). Os resultados indicam que geralmente, os graduados sentem que possuem aquelas competências, no entanto, existem algumas diferenças entre eles. Essas diferenças estão associadas ao nível de formação e instituições do ensino superior. Por exemplo, os graduados com uma licenciatura consideram ter um melhor nível no domínio dos "conhecimentos de Gestão/GRH", enquanto os que possuem um mestrado sentem-se mais confiantes no que diz respeito às línguas e autonomia. Por seu lado, os graduados de instituições orientadas para a prática, como um politécnico, sentem-se mais confiantes por exemplo na sua capacidade de liderança e de organização, enquanto os que frequentaram universidades revelaram sentir-se muito confiantes ao nível dos fundamentos teóricos. Esta pesquisa destaca a importância do ensino superior no papel de transmissor de competências aos indivíduos e a importância da sua aproximação com o mundo do trabalho. Outras fontes de aquisição de competências referidas são a experiência profissional e a formação, no entanto, este estudo não apresenta resultados conclusivos relativamente à formação. This study attempts to assess young graduates’ skills from employed in human resource management jobs. It is based on self-assessment of key skills and communication skills. The goal is to identify types of skill where graduates feel better and less prepared, as well as where they have acquired those skills. The data were collected from an original survey filled by young graduates employed or in an internship programme (n=170). The findings indicate that graduates generally perceive that they are endowed with such skills; there are however some differences. Those differences arise from level of education and higher education institutions where they graduated. For example, undergraduates feel better prepared in management and human resources management knowledge, while postgraduates (master) are more confident about languages and ability to work with autonomy. Furthermore, graduates from vocational institutions, such polytechnic school, point to abilities such as leadership and organisation, whereas universities tend to develop theoretical foundations. This research underlines the role of higher education institutions in the development of skills and the need to close the ties with the world of work. As for other sources of skills, notably professional experience and training, our findings are inconclusive regarding to training.

Mestrado em Ensino de Inglês e de Língua Estrangeira (Espanhol) no 3º Ciclo do Ensino Básico e no Ensino Secundário O presente relatório resulta de um trabalho implementado numa turma de 10.º ano de espanhol iniciação, composta pela junção de cinco turmas diferentes, no Agrupamento de Escolas Templários, no ano letivo 2015/2016, e centra-se no desenvolvimento da interação oral mediante o uso de atividades lúdicas. De forma a poder demonstrar os benefícios do lúdico para o desenvolvimento da interação oral e de um ambiente de aprendizagem aprazível, foi realizado um estudo de caso, durante a Prática de Ensino Supervisionada. Ciente da importância do desenvolvimento da oralidade e mais especificamente da interação oral no ensino de uma língua estrangeira, implementei um projeto de intervenção que permitisse o desenvolvimento de atividades diversificadas, que pretendiam ser lúdicas e promover o trabalho colaborativo e interativo dos discentes. De forma a poder avaliar as atividades desenvolvidas, foram realizados vários inquéritos por questionário aos alunos, que permitiram recolher dados sobre, inicialmente, a percepção e a opinião dos discentes sobre as atividades de interação oral e, de seguida, sobre a eficácia das atividades propostas, em especial se permitiram desenvolver a ludicidade e a interação oral. A análise dos dados recolhidos permitiu salientar o facto de as atividades lúdicas serem benéficas para o desenvolvimento da interação oral, na medida em que contribuíram para o desenvolvimento da expressão oral dos alunos e a criação de um ambiente motivador no qual os discentes foram perdendo o medo de errar e tecendo relações mais amigáveis com os seus pares. This report results from a work implemented in a class of 11th year of Beginner Spanish level, composed by the junction of five different classes, in the Agrupamento de Escolas Templários in the academic year of 2015/2016 and focuses on the development of oral interaction through the use of ludic activities. In order to be able to demonstrate the benefits of the ludic in the development of oral interaction and a pleasant learning environment, a case study was carried out during the supervised teaching practice. Aware of the importance of the development of oral communication and more specifically the oral interaction in the teaching of a foreign language, I tried to implement an intervention project that would allow the development of diversified activities, which claimed to be ludic and to promote the collaborative and interactive work of students. In order to assess these activities, numerous surveys, in the form of a questionnaire, were conducted and answered by the students, that allowed me to collect data, initially, on the students’ perception and opinion about the activities of oral interaction evolved and then on the effectiveness of the proposed activities, by trying to understand if they developed both the ludicity and oral interaction. The analysis of the data collected, allowed to highlight the fact that ludic activities are beneficial to the development of oral interaction, as they contribute to the development of oral expression of the students and to the creation of a motivating environment in which students were losing the fear of making mistakes and weaving friendlier relations with their counterparts. vii

Balanced chromosomal translocations are found in one out of 500 subjects in the general population. They usually do not carry any phenotypic consequences, except for possible infertility and for the production of unbalanced gametes leading to spontaneous abortions or chromosomal syndromes in the offspring. An association between chromosomal rearrangements and increased apoptosis markers has been demonstrated on a global scale in sperm samples of translocation and inversion carriers. In order to specify which kind of sperm cells is subject to an increased apoptosis process, this present study was aimed to analyse both chromosomal segregation and DNA fragmentation, sperm cell by sperm cell.Six patients carrying a chromosomal rearrangement (three reciprocal translocations, two Robertsonian translocations, and one chromosomal pericentric inversion) were included in a retrospective manner. Both DNA fragmentation and chromosomal segregation in spermatozoa were evaluated simultaneously using a modified TUNEL assay associated with FISH. Two thousand spermatozoa were analysed for each patient.We showed a higher proportion of spermatozoa with fragmented DNA among the unbalanced sperm cells, compared to the balanced ones, in all six patients.These results suggest an increased fragility of unbalanced spermatozoa to exogenous fragmentation factors. The exact mechanisms of those processes remain to be elucidated.