RESUMO
STUDY QUESTION: How efficacious is transplantation of ovarian cortex previously exposed to chemotherapy? SUMMARY ANSWER: Prior exposure to chemotherapy did not disrupt the function of cryopreserved ovarian tissue after transplantation. WHAT IS KNOWN ALREADY: Ovarian tissue cryopreservation (OTC) followed by ovarian tissue transplantation (OTT) is an efficacious technique for restoration of female fertility. At least 130 children have been born following this procedure. To date, little is known about the efficacy of OTT in patients exposed to cancer chemotherapy prior to OTC. STUDY DESIGN, SIZE, DURATION: This study evaluates the recovery of ovarian function and fertility in 31 consecutive patients who had received OTT, between 2005 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Thirty one patients, wanting children, were transplanted with autologous ovarian cortex, among which 22 patients (71%) had been exposed to chemotherapy before OTC. Recovery of ovarian function was considered total once menstruation occurred. Ovarian function recovery (OFR), ovarian graft survival, and incidence of pregnancy were related to previous chemotherapy exposure, type of chemotherapy and graft characteristics (number of grafted fragments and follicular density). MAIN RESULTS AND ROLE OF CHANCE: The amount of ovarian tissue collected was the only parameter to show any significant change between patients with versus without previous chemotherapy. At 1 year after OTT, the cumulative incidence of OFR was 83% (93% in patients exposed to chemotherapy and 67% in others (P = 0.14)). A low follicular density (<0.3 foll/mm2) in the transplant and a low number of grafted fragments (<16) were significantly associated with a delayed OFR. Graft survival at 2 years after OTT was 77%. It was significantly lower in patients exposed to bifunctional alkylating agents before ovarian cryopreservation and in patients with a low follicular density. The proportion of women who succeeded in having at least one live birth was 23% in the total population, 0% (0/9) in the group 'no previous chemotherapy', and 32% (7/22) in the group 'previous chemotherapy'. The cumulative incidence of pregnancy (Kaplan-Meier) at 3 years after OTT was 36% overall and 49% in case of previous chemotherapy, with no difference related to previous chemotherapy exposure. In total there were 13 pregnancies and 8 births in 7 patients. LIMITATIONS, REASONS FOR CAUTION: The pathology in the two groups of patients was not comparable. In the group of patients who had chemotherapy before OTC, there were 95% of hematological malignancies. In the group of patients who did not have chemotherapy before OTC only 1 out of 9 patients had a malignant hematological disease while 44% had some pathology affecting the ovaries. Few women are available for study and only large changes are likely to have statistical significance. WIDER IMPLICATIONS OF THE FINDINGS: These results suggest that prior cancer chemotherapy should no longer be considered a limitation to cryopreservation of ovarian tissue and current recommendations in this regard should be revised. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Agence de la Biomédecine (France's biomedical office). There are no competing interests to report. TRIAL REGISTRATION NUMBER: NCT02184806.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Criopreservação , Preservação da Fertilidade/métodos , Neoplasias/tratamento farmacológico , Ovário/transplante , Adolescente , Adulto , Autoenxertos/efeitos dos fármacos , Autoenxertos/fisiologia , Autoenxertos/transplante , Coeficiente de Natalidade , Sobreviventes de Câncer/estatística & dados numéricos , Feminino , Sobrevivência de Enxerto , Humanos , Nascido Vivo , Menstruação/fisiologia , Ovário/efeitos dos fármacos , Ovário/fisiologia , Gravidez , Recuperação de Função Fisiológica/efeitos dos fármacos , Fatores de Tempo , Transplante Autólogo/métodos , Resultado do Tratamento , Adulto JovemRESUMO
T-cell acute lymphoblastic leukemia (T-ALL) results from leukemic transformation of T-cell precursors arrested at specific differentiation stages, including an 'early-cortical' thymic maturation arrest characterized by expression of cytoplasmic TCRß but no surface T-cell receptor (TCR) and frequent ectopic expression of the TLX1/3 NK-like homeotic proteins (NKL). We designed a TCRα VJC PCR to identify clonal TCRα rearrangements in 32% of 127 T-ALLs, including 0/52 immature/TCRγδ lineage cases and 41/75 (55%) TCRαß lineage cases. Amongst the latter, TCRα rearrangements were not identified in 30/54 (56%) of IMß/pre-αß early-cortical T-ALLs, of which the majority (21/30) expressed TLX1/3. We reasoned that the remaining T-ALLs might express other NKL proteins, so compared transcript levels of 46 NKL in T-ALL and normal thymic subpopulations. Ectopic overexpression of 10 NKL genes, of which six are unreported in T-ALL (NKX2-3, BARHL1, BARX2, EMX2, LBX2 and MSX2), was detectable in 17/104 (16%) T-ALLs. Virtually all NKL overexpressing T-ALLs were TCRα unrearranged and ectopic NKL transcript expression strongly repressed Eα activity, suggesting that ectopic NKL expression is the major determinant in early-cortical thymic T-ALL maturation arrest. This immunogenetic T-ALL subtype, defined by TCRß VDJ but no TCRα VJ rearrangement, is associated with a favorable outcome in GRAALL-treated adult T-ALLs.
Assuntos
Proteínas de Homeodomínio/metabolismo , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Adulto , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Feminino , Células HeLa , Humanos , MasculinoAssuntos
Biomarcadores Tumorais/genética , Transtornos Plaquetários/complicações , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/etiologia , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Adolescente , Adulto , Transtornos Plaquetários/genética , Plaquetas/patologia , Criança , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Linhagem , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , PrognósticoAssuntos
Antineoplásicos/uso terapêutico , Doenças Cardiovasculares/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Pirimidinas/uso terapêutico , Medição de Risco/métodos , Adulto , Idoso , Algoritmos , Antineoplásicos/efeitos adversos , Doenças Cardiovasculares/diagnóstico , Ensaios Clínicos Fase III como Assunto , Análise Mutacional de DNA , Intervalo Livre de Doença , Europa (Continente) , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
Allogeneic hematopoietic stem cell transplantation provides the best chance of long-term survival for patients with AML, but is associated with an unpredictable risk of treatment-related mortality. From January 2000 to December 2010, we compared the outcomes for patients with AML aged 35 and over using reduced-intensity conditioning (RIC, N=60) or conventional myeloablative conditioning (MAC) regimen (N=72) transplantation. The median follow-up was 47 months (10-134). The 4-year cumulative incidence of non-relapse mortality was 21%. After adjusting for cytogenetic risk, gender donor/recipient mismatch and CD34+ cells, non-relapse mortality was significantly lower with the RIC regimen (P=0.027). The 4-year cumulative incidence of relapse was 38% and no difference was observed in the adjusted relapse rate between the two groups. The 4-year OS rate was 46%. Using both Cox regression and inverse probability-of-treatment weighted (IPTW) method, a similar OS rate was found with both regimens (adjusted hazard ratios for conventional vs reduced of 1.14 (95% CI 0.67-1.93, P=0.64) with Cox regression, and 1.14 (95% CI 0.55-2.34, P=0.73) with IPTW). Until prospective trials are completed, this study supports the use of a reduced-intensity regimen prior to transplantation for patients with AML aged 35 and over.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante , Adulto , Fatores Etários , Idoso , Aloenxertos , Intervalo Livre de Doença , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Taxa de SobrevidaRESUMO
The impact of allelic HLA matching in patients with AML and myelodysplastic syndrome (MDS) who receive allogeneic PBSC after a reduced-intensity conditioning (RIC) regimen is unclear. From January 2000 to December 2010, 108 consecutive patients with AML (n=63) and MDS (n=45) received PBSC after RIC in our center, either from siblings (n=70) or from matched unrelated donors (MUD; 10/10 high resolution, n=38). Conditioning regimen was fludarabine based in 95% of patients and GvHD prophylaxis was mostly cyclosporine plus mycophenolate. Patient characteristics were similar between sibling and MUD for age (median 57 years), gender and disease distribution. Conditioning regimen (more anti-thymocyte globulin (ATG) in MUD), donor age (younger for MUD) and number of CD34+ cells infused (higher in MUD) were different. The median follow-up was 36 months (range 2-72). Engraftment, GvHD, TRM, relapse rate and OS at 3 years were comparable between sibling and MUD. After adjustment for age, cytogenetic risk, ATG and number of CD34+ cells infused, donor type still did not influence OS. In patients with AML or MDS, HSCT from MUD using PBSC after a RIC regimen led to similar outcomes than from Siblings.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/cirurgia , Síndromes Mielodisplásicas/tratamento farmacológico , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doadores de Tecidos , Transplante Autólogo , Resultado do Tratamento , Doadores não Relacionados , Adulto JovemRESUMO
Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French-American-British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P = 0.02) and overall survival (5-year OS: 23% vs 45%, P = 0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.
Assuntos
Biomarcadores Tumorais/genética , Análise Citogenética , DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Mutação/genética , Adolescente , Adulto , DNA Metiltransferase 3A , DNA de Neoplasias/genética , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/classificação , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Reação em Cadeia da Polimerase , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
The use of steroids is not required in myeloid malignancies and remains controversial in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). We sought to evaluate dexamethasone in patients with ALI/ARDS caused by acute monocytic leukaemia (AML FAB-M5) via either leukostasis or leukaemic infiltration. Dexamethasone (10 mg every 6 h until neutropenia) was added to chemotherapy and intensive care unit (ICU) management in 20 consecutive patients between 2005 and 2008, whose data were compared with those from 20 historical controls (1994-2002). ICU mortality was the primary criterion. We also compared respiratory deterioration rates, need for ventilation and nosocomial infections. 17 (85%) patients had hyperleukocytosis, 19 (95%) had leukaemic masses, and all 20 had severe pancytopenia. All patients presented with respiratory symptoms and pulmonary infiltrates prior to AML FAB-M5 diagnosis. Compared with historical controls, dexamethasone-treated patients had a significantly lower ICU mortality rate (20% versus 50%; p = 0.04) and a trend for less respiratory deterioration (50% versus 80%; p = 0.07). There were no significant increases in the rates of infections with dexamethasone. In conclusion, in patients with ALI/ARDS related to AML FAB-M5, adding dexamethasone to conventional chemotherapy seemed effective and safe. These results warrant a controlled trial of dexamethasone versus placebo in AML FAB-M5 patients with noninfectious pulmonary infiltrates.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Antineoplásicos/uso terapêutico , Dexametasona/uso terapêutico , Leucemia Monocítica Aguda/complicações , Leucemia Monocítica Aguda/tratamento farmacológico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Lesão Pulmonar Aguda/mortalidade , Adulto , Idoso , Feminino , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Leucemia Monocítica Aguda/mortalidade , Infiltração Leucêmica/tratamento farmacológico , Leucostasia/induzido quimicamente , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pancitopenia/tratamento farmacológico , Respiração Artificial/estatística & dados numéricos , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/mortalidade , Testes de Função Respiratória , Índice de Gravidade de Doença , Resultado do TratamentoAssuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Polimorfismo de Nucleotídeo Único/genética , Proteínas WT1/genética , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
PURPOSE: Human herpesvirus 6 (HHV6) is an emerging cause of interstitial pneumonia in immunocompromised hosts. However, the clinical significance of a positive PCR test for HHV6 in respiratory samples from patients with hematological malignancies remains unclear. METHODS: We retrospectively studied the features and outcomes of 29 critically ill hematology patients with acute respiratory failure and lung pulmonary infiltrates visible on a chest radiograph, who tested positive for a qualitative PCR for HHV6 in bronchoalveolar lavage fluid. RESULTS: Of the 29 patients, 18 (62%) were stem cell transplant recipients and 11 (38%) had received chemotherapy. All patients had a fever. Clinical manifestations consistent with extra-pulmonary HHV6 disease were noted in 17 (59%) patients. One or more co-pathogens were found in 25 (86%) patients. The four remaining patients diagnosed with HHV6 pneumonia and subsequently recovered with foscarnet therapy. Antiviral therapy was also given to seven patients with co-infections, of whom two ultimately died. CONCLUSIONS: In most cases, HHV6 recovered from BAL fluid is a co-pathogen whose clinical relevance remains undetermined. However, in some cases, HHV6 is the only pathogen, along with disseminated systemic viral disease, and the patient is likely to benefit from foscarnet therapy.
Assuntos
Líquido da Lavagem Broncoalveolar/virologia , Herpesvirus Humano 6/isolamento & purificação , Herpesvirus Humano 6/patogenicidade , Síndrome do Desconforto Respiratório/virologia , Adulto , Transplante de Medula Óssea/patologia , Broncoscopia/métodos , Feminino , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/virologia , Hematologia , Herpesvirus Humano 6/crescimento & desenvolvimento , Humanos , Hospedeiro Imunocomprometido , Unidades de Terapia Intensiva , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Pneumonia/virologia , Reação em Cadeia da Polimerase , Síndrome do Desconforto Respiratório/complicações , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Leukemia-initiating/repopulating cells (LICs), also named leukemic stem cells, are responsible for propagating human acute leukemia. Although they have been characterized in various leukemias, their role in T-cell acute lymphoblastic leukemia (T-ALL) is unclear. To identify and characterize LICs in T-ALL (T-LIC), we fractionated peripheral blood cell populations from patient samples by flow cytometry into three cell fractions by using two markers: CD34 (a marker of immature cells and LICs) and CD7 (a marker of early T-cell differentiation). We tested these populations in both in vitro culture assays and in vivo for growth and leukemia development in immune-deficient mice. We found LIC activity in CD7(+) cells only as CD34(+)CD7(-) cells contained normal human progenitors and hematopoietic stem cells that differentiated into T, B lymphoid and myeloid cells. In contrast, CD34(+)CD7(+) cells were enriched in LICs, when compared with CD34(-)CD7(+) cells. These CD34(+)CD7(+) cells also proliferated more upon NOTCH activation than CD34(-)CD7(+) cells and were sensitive to dexamethasone and NOTCH inhibitors. These data show that CD34 and CD7 expression in human T-ALL samples help in discriminating heterogeneous cell populations endowed with different LIC activity, proliferation capacity and responses to drugs.
Assuntos
Antígenos CD34/análise , Antígenos CD7/análise , Células-Tronco Neoplásicas/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Animais , Proliferação de Células , Dexametasona/farmacologia , Hematopoese , Humanos , Camundongos , Camundongos Endogâmicos NOD , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Receptores Notch/fisiologia , Transdução de SinaisRESUMO
Pyoderma gangrenosum (PG) is a non-infectious purulent ulcerative disease triggered mainly by chronic inflammatory bowel disease, monoclonal gammapathy, polyarthritis and haematological malignancies; exceptionally, it can be triggered by surgery alone. When PG is associated with fever, it can mimic infectious cellulitis. When it is located on the breast, unnecessary and deleterious surgical debridement may be performed. We present two cases of PG of the breast. The first is a postoperative PG and the second was associated with acute myeloid leukaemia - both led to unnecessary surgery. Several elements may have helped to make the diagnosis: nipples little affected by PG, symmetrical lesions on both breasts, other similar lesions elsewhere on the body, resistance to wide spectrum antibiotherapy, complete blood count abnormalities and negativity of bacterial culture. We propose an index to help the surgeon in his decision to realise a surgical debridement or to postpone it and consider the diagnosis of PG.
Assuntos
Mama/patologia , Leucemia Mieloide Aguda/diagnóstico , Mastectomia/métodos , Pioderma Gangrenoso/diagnóstico , Pioderma Gangrenoso/terapia , Úlcera Cutânea/diagnóstico , Corticosteroides/uso terapêutico , Adulto , Antibacterianos/uso terapêutico , Mama/cirurgia , Terapia Combinada , Desbridamento/métodos , Diagnóstico Diferencial , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/cirurgia , Mastectomia/efeitos adversos , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/terapia , Medição de Risco , Estudos de Amostragem , Índice de Gravidade de Doença , Úlcera Cutânea/terapia , Resultado do Tratamento , Cicatrização/fisiologiaRESUMO
INTRODUCTION: In the course of acute myeloid leukaemias, pulmonary manifestations constitute diagnostic and therapeutic emergencies and contribute to the morbidity and mortality at all stages of these diseases. BACKGROUND: Specific lung involvement mainly affects patients at the onset of their disease. The characteristics of such manifestations are poorly known and have rarely been the object of dedicated publications. VIEWPOINT: The purpose of this work thus is to review the literature on the various specific lung manifestations occurring in the course of acute myeloid leukaemias.
Assuntos
Leucemia Mieloide Aguda/complicações , Pneumopatias/etiologia , HumanosRESUMO
UNLABELLED: INTRODUCTION - BACKGROUND: The non infectious pulmonary manifestations occurring in lymphoplasmocytic proliferations others than lymphomas are poorly understood and have rarely been the object of dedicated publications. VIEWPOINTS: The purpose of this work is to review the literature of the various specific lung manifestations occurring during these malignant haematological diseases. We will also consider acute lymphoblastic leukaemia, chronic lymphocytic leukaemia and hairy cell leukaemia, as well as malignant plasmocytic disorders such as myeloma, POEMS syndrome and Waldenström's macroglobulinaemia. CONCLUSION: During the course of lymphoplasmocytic diseases, lung manifestations are variable and sometimes require invasive techniques for definitive diagnosis.