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1.
Haematologica ; 107(1): 221-230, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33327711

RESUMO

Follicular lymphoma (FL) is the most common indolent lymphoma. Despite the clear benefit of CD20-based therapy, a subset of FL patients still progress to aggressive lymphoma. Thus, identifying early biomarkers that incorporate PET metrics could be helpful to identify patients with a high risk of treatment failure with Rituximab. We retrospectively included a total of 132 untreated FL patients separated into training and validation cohorts. Optimal threshold of baseline SUVmax was first determined in the training cohort (n=48) to predict progression-free survival (PFS). The PET results were investigated along with the tumor and immune microenvironment, which were determined by immunochemistry and transcriptome studies involving gene set enrichment analyses and immune cell deconvolution, together with the tumor mutation profile. We report that baseline SUVmax >14.5 was associated with poorer PFS than baseline SUVmax ≤14.5 (HR=0.28; p=0.00046). Neither immune T-cell infiltration nor immune checkpoint expression were associated with baseline PET metrics. By contrast, FL samples with Ki-67 staining ≥10% showed enrichment of cell cycle/DNA genes (p=0.013) and significantly higher SUVmax values (p=0.007). Despite similar oncogenic pathway alterations in both SUVmax groups of FL samples, 4 out of 5 cases harboring the infrequent FOXO1 transcription factor mutation were seen in FL patients with SUVmax >14.5. Thus, high baseline SUVmax reflects FL tumor proliferation and, together with Ki-67 proliferative index, can be used to identify patients at risk of early relapse with R-chemotherapy.


Assuntos
Linfoma Folicular , Linfoma não Hodgkin , Proliferação de Células , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/genética , Estudos Retrospectivos , Rituximab , Microambiente Tumoral
2.
Ann Pathol ; 41(2): 176-185, 2021 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32646777

RESUMO

INTRODUCTION: In order to validate our strategy of continuous improvement and to identify new ways to increase performance, an evaluation of all the procedures was conducted in our department using the principles of lean management. MATERIAL AND METHODS: Lean-6-sigma methodology (Gemba Walk, Value StreamMapping, spaghetti diagram, Kaizen workshop and priorization matrix) was used to analyze the procedures of the conventional and molecular sectors, and to identify bottlenecks, actions without added value and solutions. RESULTS: The audit identified bottlenecks in pre-analytical (registration), analytical (cytology, immunohistochemistry, sequencing, pathologists) and post-analytical processes (absence of secretaries, delivery of reports by mail). It underlined a suboptimal flow of people and materials, the heavy impact of an increasing work load (8%/year) in reception and microscopy even though we had outsourced, and an often critical work place schedule for technicians which prevent them from achieving tasks without added value (quality control, validation of methods and protocols) or even daily tasks (cutting, immunohistochemistry). After completing the 72 actions aimed at managing overproduction, improving working conditions and developing new activities, turn-around time was partially under control and the automation process was well advanced. DISCUSSION AND CONCLUSION: The audit validated our strategy of continuous improvement and advanced the standardization of our working conditions. Even if the turn-around time for reports was shortened, the audit initiated a positive medical and technical dynamic that should help us to implement the next steps of our reorganization (automation and extension of the department).

3.
Blood ; 132(5): 510-520, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-29871863

RESUMO

Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoproliferative disorder involving chronic NF-κB activation. Several mutations in the BCR and MyD88 signaling pathway components, such as MyD88 L265P, are implicated in this aberrant activation. Among heat shock proteins, HSP110 has recently been identified as a prosurvival and/or proliferation factor in many cancers, but its role in ABC-DLBCL survival mechanisms remained to be established. We observed that short hairpin RNA-mediated HSP110 silencing decreased the survival of several ABC-DLBCL cell lines and decreased immunoglobulin M-MyD88 co-localization and subsequent NF-κB signaling. Conversely, overexpression of HSP110 in ABC-DLBCL or non-DLBCL cell lines increased NF-κB signaling, indicating a tight interplay between HSP110 and the NF-κB pathway. By using immunoprecipitation and proximity ligation assays, we identified an interaction between HSP110 and both wild-type MyD88 and MyD88 L265P. HSP110 stabilized both MyD88 forms with a stronger effect on MyD88 L265P, thus facilitating chronic NF-κB activation. Finally, HSP110 expression was higher in lymph node biopsies from patients with ABC-DLBCL than in normal reactive lymph nodes, and a strong correlation was found between the level of HSP110 and MyD88. In conclusion, we identified HSP110 as a regulator of NF-κB signaling through MyD88 stabilization in ABC-DLBCL. This finding reveals HSP110 as a new potential therapeutic target in ABC-DLBCL.


Assuntos
Proteínas de Choque Térmico HSP110/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Fator 88 de Diferenciação Mieloide/química , NF-kappa B/metabolismo , Estudos de Coortes , Proteínas de Choque Térmico HSP110/genética , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/genética , Estabilidade Proteica , Transdução de Sinais , Células Tumorais Cultivadas
4.
Hematol Oncol ; 38(2): 137-145, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31953963

RESUMO

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a therapeutic option for patients with relapsed follicular lymphoma (FL). The clinical characteristics and outcomes of FL relapse after ASCT in the rituximab era have not yet been fully elucidated. We retrospectively reviewed 414 FL patients treated with ASCT between 2000 and 2014 in four hematology departments. All patients received rituximab as a first-line treatment. We specifically analyzed the clinical characteristics, treatment strategies at relapse, and outcomes of 95 patients (23%) who relapsed after ASCT. The patients (median age, 57 y) received a median of two lines of therapy (range, 2-6) prior to ASCT, with 92% in complete response (CR) or partial response (PR) before ASCT. Histological transformation at relapse after ASCT was observed in 20% of the patients. Treatment at relapse after ASCT consisted of chemotherapy with or without rituximab (n = 45/90, 50%), targeted agents (18%), rituximab monotherapy (14%), or consolidation allogeneic transplantation after induction chemotherapy (12%) and radiotherapy (6%). After relapse, the median progression-free survival (PFS) and overall survival (OS) were 1 year (95% CI, 0.541-1.579) and 5.5 years (95% CI, 1.910-9.099), respectively. In the multivariate analysis, histological transformation (HT) was associated with OS (P = .044; HR 2.439; 95% CI, 1.025-5.806), and a high FLIPI score at relapse was associated with PFS (P = .028; HR 2.469; 95% CI, 1.104-5.521). This retrospective study showed that the period of PFS of patients who relapsed after ASCT is short. A biopsy should be performed for these patients to document the HT. Our results indicate that new treatment strategies will need to be developed for these patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/mortalidade , Linfoma Folicular/mortalidade , Recidiva Local de Neoplasia/mortalidade , Rituximab/uso terapêutico , Adulto , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Terapia Combinada , Feminino , Seguimentos , Humanos , Linfoma Folicular/patologia , Linfoma Folicular/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Autólogo
5.
CNS Oncol ; 11(3): CNS88, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35694977

RESUMO

Primary CNS involvement is very rare in Hodgkin lymphoma. Here we present two cases of spinal cord dissemination. Two women of 40 and 65 years of age presented symptoms of spinal cord injury; imaging showed an intramedullary mass in T10 and T2, respectively, without vertebral involvement and upper diaphragmatic lymph nodes. Lymph-node biopsy confirmed the diagnosis of classical Hodgkin lymphoma in both patients. The first patient received four cycles of chemotherapy (escalated BEACOPP and ABVD) with intrathecal therapy, and the second four cycles of doxorubicin, vinblastine, dacarbazine (AVD) and local irradiation after surgery decompression. Complete metabolic response was obtained at the end of treatment. After 5 and 7 years of follow-up respectively, neurological deficits persisted in both.


Lymph-node infiltration is the most common presentation in Hodgkin lymphoma at diagnosis. Primary extranodal involvement is rare and spinal cord infiltration exceptional. Back pain, tingling and vesico-sphincter dysfunctions are the main symptoms. 18F-fluorodeoxyglucose (FDG) PET and MRI can detect the location and extension of neurological involvement. We present here two cases of tumoral myelitis and a review of the literature. Local treatment (surgery/radiotherapy) is often administered together with chemotherapy to optimize local control and to avoid long-term sequelae.


Assuntos
Doença de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/uso terapêutico , Dacarbazina/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/terapia , Humanos , Medula Espinal/patologia , Vimblastina/uso terapêutico , Vincristina/uso terapêutico
6.
Artigo em Inglês | MEDLINE | ID: mdl-33608382

RESUMO

Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) is usually straightforward, involving clinical, immunophenotypic (Matutes score), and (immuno)genetic analyses (to refine patient prognosis for treatment). CLL cases with atypical presentation (e.g., Matutes ≤ 3) are also encountered, and for these diseases, biology and prognostic impact are less clear. Here we report the genomic characterization of a case of atypical B-CLL in a 70-yr-old male patient; B-CLL cells showed a Matutes score of 3, chromosomal translocation t(14;18)(q32;q21) (BCL2/IGH), mutated IGHV, deletion 17p, and mutations in BCL2, NOTCH1 (subclonal), and TP53 (subclonal). Quite strikingly, a novel PAX5 mutation that was predicted to be loss of function was also seen. Exome sequencing identified, in addition, a potentially actionable BRAF mutation, together with novel somatic mutations affecting the homeobox transcription factor NKX2-3, known to control B-lymphocyte development and homing, and the epigenetic regulator LRIF1, which is implicated in chromatin compaction and gene silencing. Neither NKX2-3 nor LRIF1 mutations, predicted to be loss of function, have previously been reported in B-CLL. Sequencing confirmed the presence of these mutations together with BCL2, NOTCH1, and BRAF mutations, with the t(14;18)(q32;q21) translocation, in the initial diagnostic sample obtained 12 yr prior. This is suggestive of a role for these novel mutations in B-CLL initiation and stable clonal evolution, including upon treatment withdrawal. This case extends the spectrum of atypical B-CLL with t(14;18)(q32;q21) and highlights the value of more global precision genomics for patient follow-up and treatment in these patients.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Epigênese Genética , Proteínas de Homeodomínio/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Fator de Transcrição PAX5/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Fatores de Transcrição/genética , Idoso , Proteínas de Ciclo Celular/genética , Evolução Clonal , Proteínas de Homeodomínio/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Fator de Transcrição PAX5/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptor Notch1/genética , Fatores de Transcrição/metabolismo , Translocação Genética , Proteína Supressora de Tumor p53/genética , Sequenciamento do Exoma
7.
J Clin Med ; 7(11)2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445692

RESUMO

Cystic echinococcosis (CE) is a cosmopolitan parasitic zoonosis affecting more than one million people worldwide. In humans, primary bone CE is rare and involvement of E. ortleppi is very uncommon. We report here the first case of primary vertebral cystic echinococcosis due to E. ortleppi in Burgundy, France.

8.
Nat Commun ; 9(1): 1431, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29650953

RESUMO

Heat shock protein 27 (HSP27/HSPB1) is a stress-inducible chaperone that facilitates cancer development by its proliferative and anti-apoptotic functions. The OGX-427 antisense oligonucleotide against HSP27 has been reported to be beneficial against idiopathic pulmonary fibrosis. Here we show that OGX-427 is effective in two murine models of thrombopoietin- and JAKV617F-induced myelofibrosis. OGX-427 limits disease progression and is associated with a reduction in spleen weight, in megakaryocyte expansion and, for the JAKV617F model, in fibrosis. HSP27 regulates the proliferation of JAK2V617F-positive cells and interacts directly with JAK2/STAT5. We also show that its expression is increased in both CD34+ circulating progenitors and in the serum of patients with JAK2-dependent myeloproliferative neoplasms with fibrosis. Our data suggest that HSP27 plays a key role in the pathophysiology of myelofibrosis and represents a new potential therapeutic target for patients with myeloproliferative neoplasms.


Assuntos
Proteínas de Choque Térmico HSP27/genética , Janus Quinase 2/genética , Oligonucleotídeos/farmacologia , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Fator de Transcrição STAT5/genética , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Transplante de Medula Óssea , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células HEK293 , Proteínas de Choque Térmico HSP27/imunologia , Humanos , Janus Quinase 2/imunologia , Células K562 , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Terapia de Alvo Molecular , Mutação , Mielofibrose Primária/imunologia , Mielofibrose Primária/patologia , Fator de Transcrição STAT5/imunologia , Trombopoetina/genética , Trombopoetina/imunologia , Transdução Genética , Irradiação Corporal Total
9.
PLoS One ; 10(10): e0141010, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26501981

RESUMO

Calreticulin (CALR) mutations have recently been reported in 70-84% of JAK2V617F-negative myeloproliferative neoplasms (MPN), and this detection has become necessary to improve the diagnosis of MPN. In a large single-centre cohort of 298 patients suffering from Essential Thrombocythemia (ET), the JAK2V617F, CALR and MPL mutations were noted in 179 (60%), 56 (18.5%) and 13 (4.5%) respectively. For the detection of the CALR mutations, three methods were compared in parallel: high-resolution melting-curve analysis (HRM), product-sizing analysis and Sanger sequencing. The sensitivity for the HRM, product-sizing analysis and Sanger sequencing was 96.4%, 98.2% and 89.3% respectively, whereas the specificity was 96.3%, 100% and 100%. In our cohort, the product-sizing analysis was the most sensitive method and was the easiest to interpret, while the HRM was sometimes difficult to interpret. In contrast, when large series of samples were tested, HRM provided results more quickly than did the other methods, which required more time. Finally, the sequencing method, which is the reference method, had the lowest sensitivity but can be used to describe the type of mutation precisely. Altogether, our results suggest that in routine laboratory practice, product-sizing analysis is globally similar to HRM for the detection of CALR mutations, and that both may be used as first-line screening tests. If the results are positive, Sanger sequencing can be used to confirm the mutation and to determine its type. Product-sizing analysis provides sensitive and specific results, moreover, with the quantitative measurement of CALR, which might be useful to monitor specific treatments.


Assuntos
Neoplasias da Medula Óssea/diagnóstico , Calreticulina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Medula Óssea/genética , Feminino , Mutação da Fase de Leitura/genética , Humanos , Mutação INDEL/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Sensibilidade e Especificidade , Análise de Sequência/métodos , Adulto Jovem
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