RESUMO
Hodgkin lymphoma (HL) is an uncommon B-cell malignant disease. It usually presents with mediastinal and/or laterocervical lymph node localization, while primary extranodal HL is a rare entity giving rise to diagnostic and therapeutic challenges. It rarely presents as just extranodal localization, so its presence within the maxillary sinus without any lymphadenopathy is exceptional. Given the rarity of this localization, there is no standard treatment for maxillary sinus HL. We present a case of a patient with extranodal HL of the right maxillary sinus treated with primary surgery followed by adjuvant sequential chemoradiation therapy.
Assuntos
Doença de Hodgkin , Humanos , Seio Maxilar/cirurgia , Terapia Combinada , Maxila , QuimiorradioterapiaRESUMO
Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood-brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.
Assuntos
Linfoma de Célula do Manto , Masculino , Adulto , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Linfoma de Célula do Manto/patologia , Pirimidinas , Estudos Retrospectivos , Pirazóis/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do Tratamento , Sistema Nervoso Central/patologiaRESUMO
The development of drugs able to target BTK, PI3k-delta and BCL2 has dramatically improved chronic lymphocytic leukaemia (CLL) therapies. However, drug resistance to these therapies has already been reported due to non-recurrent changes in oncogenic pathways and genes expression signatures. In this study, we investigated the cooperative role of the BCL2 inhibitor venetoclax and the BRD4 inhibitor JQ1. In particular, we found that JQ1 shows additional activity with venetoclax, in CLL cell lines and in ex vivo isolated primary CD19+ lymphocytes, arguing in favour of combination strategies. Lastly, JQ1 is also effective in venetoclax-resistant CLL cell lines. Together, our findings indicated that the BET inhibitor JQ1 could be a promising therapy in CLL, both as first-line therapy in combination with venetoclax and as second-line therapy, after the emergence of venetoclax-resistant clones.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Azepinas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Sulfonamidas/farmacologia , Fatores de Transcrição/metabolismo , Triazóis/farmacologiaRESUMO
Philadelphia positive acute lymphoblastic leukemia is well documented nowadays but very little is known about Philadelphia positive lymphoblastic lymphoma (LBL). Only two cases are available in literature and both of them died during treatment whereas the patient treated in our center is still alive 3 years after the initial diagnosis. A chemo-free regimen was used in induction with dasatinib plus steroids with local radiotherapy on the mass, and then the patient underwent bone marrow transplant. Philadelphia positive lymphoblastic lymphoma is a difficult diagnosis to make and the management of this extremely rare disease is very challenging.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Decitabina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão/métodos , Sulfonamidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Terapia de Salvação/métodos , Resultado do TratamentoAssuntos
Anemia Aplástica/complicações , Transfusão de Sangue , Neoplasias Hematológicas/complicações , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Anemia Aplástica/sangue , Anemia Aplástica/diagnóstico , Anemia Aplástica/terapia , Terapia por Quelação , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Humanos , Quelantes de Ferro/administração & dosagem , Sobrecarga de Ferro/diagnóstico , Masculino , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Células da Medula Óssea/metabolismo , Eritropoetina/biossíntese , Síndromes Mielodisplásicas/metabolismo , Receptores da Transferrina/biossíntese , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/patologia , Eritropoetina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Prognóstico , Receptores da Transferrina/genética , Estudos RetrospectivosRESUMO
Meningioma 1 (MN1) gene overexpression has been reported in acute myeloid leukaemia (AML) patients and identified as a negative prognostic factor. In order to characterize patients presenting gene overexpression and to verify if MN1 transcript could be a useful marker for minimal residual disease detection, MN1 was quantified in 136 AML patients with different cytogenetic risk and in 50 normal controls. In 20 patients bearing a fusion gene transcript suitable for minimal residual disease quantitative assessment and in 8 patients with NPM1 mutation, we performed a simultaneous analysis of MN1 and the fusion-gene transcript or NPM1 mutation during follow-up. Sequential MN1 and WT1 analysis was also performed in 13 AML patients lacking other molecular markers. The data obtained show that normal cells consistently express low levels of MN1 transcript. In contrast, high levels of MN1 expression are present in 47% of patients with normal karyotype and in all cases with inv(16). MN1 levels during follow-up were found to follow the pattern of other molecular markers (fusion gene transcripts, NPM1 and WT1). Increased MN1 expression in the BM during follow up was always found to be predictive of an impending hematological relapse.
Assuntos
Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Leucemia Mieloide Aguda/classificação , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Nucleofosmina , Transativadores , Adulto JovemRESUMO
The Wilms tumor gene WT1 is a useful marker of clonal hematopoiesis and it has been shown to be a good marker of residual disease and it reflects the response to therapy. Although myelofibrosis is characterized by mutations of JAK2 and calreticulin (CALR), these mutations are not useful to monitor response to therapy. In this study we demonstrated that in patients affected by myelofibrosis WT1 correlates with the International Prognostic Scoring System (IPSS) score at diagnosis. Furthermore WT1 is a good marker of response to JAK2 inhibitors especially for patients without blasts and for patients who develop anemia or thrombocytopenia not for progression but as therapy related toxicity. Finally, WT1 transcript reduction can mirror a benefit of therapy on the disease burden. This study demonstrated that WT1 is a good marker for monitoring the response to therapy in patients affected by myelofibrosis.
Assuntos
Expressão Gênica , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/genética , Proteínas WT1/genética , Biomarcadores , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Mutação , Mielofibrose Primária/terapia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Mutations of the BCR-ABL1 fusion gene represent a well established cause of resistance to tyrosine kinase inhibitors. Among the different mutations identified T315I is of particular concern since it is not effectively targeted by the majority of Tyrosine Kinase Inhibitors so far available. We developed a novel assay based on peptide nucleic acid (PNA) technology coupled to immunofluorescence microscopy (PNA-FISH) for the specific detection at a single cell level of BCR-ABL (T315I) mutation thus improving both, diagnostic resolution and the study of clonal prevalence. Furthermore we developed an additional method based on PNA directed PCR-clamping for the fast and easy detection of the mutation. RESULTS: The PNA directed PCR clamping allows to detect an amount of mutated template as low as 0.5 %. This method is highly sensitive, specific and cheap and could be applied even in laboratory not equipped for more sophisticated analysis. Furthermore, the PNA FISH method allows to identify a small amount of progenitor cells still present after therapy with specific inhibitors. CONCLUSIONS: We present here two different methods based on PNA for the detection of T315I useful for different purposes. PNA-FISH can be used to study clonal evolution. In addition, this method could help in the study of compound mutations being able to identify two different mutations in a single cell. PNA directed PCR clamping although not superior to sequencing can be applied worldwide even in laboratory not equipped to search for mutations.
Assuntos
Adenocarcinoma/prevenção & controle , Anticorpos Antineoplásicos/biossíntese , Vacinas Anticâncer/administração & dosagem , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Neoplasias da Próstata/prevenção & controle , Proteínas WT1/administração & dosagem , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Animais , Vacinas Anticâncer/biossíntese , Vacinas Anticâncer/imunologia , Modelos Animais de Doenças , Adjuvante de Freund/administração & dosagem , Glutationa Transferase/administração & dosagem , Glutationa Transferase/biossíntese , Glutationa Transferase/imunologia , Humanos , Masculino , Camundongos , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Vacinação , Proteínas WT1/biossíntese , Proteínas WT1/imunologiaRESUMO
In the elderly patients, where biopsy-induced complications could outweigh the benefit, the identification of pancreatic masses is generally referred to as a synonymous of pancreatic cancer and patients are dismissed with no further options than palliative and supportive care. Notwithstanding, not all pancreatic tumors are cancers and therefore alternative diagnoses need to be investigated, especially when patients are unfit for invasive diagnostic procedures. Here, we report a case of an aged patient that was admitted to an internal medicine division for a previously diagnosed pancreatic cancer. The reassessment of the diagnosis has allowed identifying the pancreatic mass as a manifestation of focal pancreatitis in the context of an IgG4-related disease. Accordingly, patient was treated with steroids with rapid clinical improvement. This clinical case suggests that autoimmune diseases should always be considered in the differential diagnosis of pancreatic masses of the elderly.
RESUMO
BACKGROUND: Mutation(s) of the JAK2 gene (V617F) has been described in a significant proportion of Philadelphia negative Myeloproliferative Neoplasms (MPN) patients and its detection is now a cornerstone in the diagnostic algorithm. METHODS: We developed a novel assay based on peptide nucleic acid (PNA) technology coupled to immuno-fluorescence microscopy (PNA-FISH) for the specific detection at a single cell level of JAK2-mutation thus improving both the diagnostic resolution and the study of clonal prevalence. RESULTS: Using this assay we found a percentage of mutated CD34+ cells ranging from 40% to 100% in Polycythemia Vera patients, from 15% to 80% in Essential Thrombocythemia and from 25% to 100% in Primary Myelofibrosis. This method allows to distinguish, with a high degree of specificity, at single cell level, between CD34+ progenitor stem cells harbouring the mutated or the wild type form of JAK2 in NPM patients. CONCLUSIONS: This method allows to identify multiple gene abnormalities which will be of paramount relevance to understand the pathophysiology and the evolution of any type of cancer.
Assuntos
Janus Quinase 2/genética , Microscopia de Fluorescência/métodos , Mutação , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Ácidos Nucleicos Peptídicos , Separação Celular , Citometria de Fluxo , Humanos , Reação em Cadeia da PolimeraseRESUMO
Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder with systemic symptoms and poor prognosis and is characterized by an abnormal proliferation of polyclonal plasmablasts in the mantle zone of B-cell follicles. The disease is found primarily in chronic HIV carriers and is usually strictly associated with human herpes virus type 8 (HHV-8) coinfection, which is believed to play a key role in the pathogenesis of MCD. The disease is also diagnosed in HIV-negative patients, who are usually elderly or immunosuppressed; however, in about half of these cases, no evidence of HHV8 infection is found. The anti-CD20 monoclonal antibody rituximab is now the preferred treatment for HIV-positive MCD. However, it is not clear whether rituximab is effective in HIV-negative patients with MCD, particularly in the HHV8-positive subset. We report here the clinical and biologic courses of two HIV-negative, HHV8-positive patients with MCD who were treated with rituximab. In both cases, a significant clinical improvement was observed after the first two infusions, which was shortly followed by a drop in HHV8 viremia to undetectable levels. Both patients underwent complete clinical remission, which persisted without relapse at 30 and 9 months of follow-up, respectively. No reactivation of the Kaposi sarcoma found in a lymph node of one of the patients was observed. Our report, along with additional data present in the literature, suggests that rituximab may be an appropriate and safe first-line therapy for HIV-negative, HHV8-positive MCD.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Hiperplasia do Linfonodo Gigante , Herpesvirus Humano 8 , Sarcoma de Kaposi , Idoso , Anticorpos Monoclonais Murinos , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/virologia , Soronegatividade para HIV , Humanos , Masculino , Indução de Remissão , Rituximab , Sarcoma de Kaposi/tratamento farmacológico , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/virologia , Prevenção SecundáriaAssuntos
Abdome/fisiopatologia , Herpes Zoster/patologia , Íleus , Paraplegia/fisiopatologia , Mielofibrose Primária , Idoso , Comorbidade , Estado Terminal , Humanos , MasculinoAssuntos
Anticorpos Antineoplásicos/sangue , Neoplasias Hematológicas/imunologia , Proteínas WT1/imunologia , Estudos de Casos e Controles , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Leucemia/imunologia , Síndromes Mielodisplásicas/imunologia , Transtornos Mieloproliferativos/imunologia , Proteínas Recombinantes/imunologiaRESUMO
The introduction of the BCR-ABL kinase inhibitor, imatinib mesylate (Gleevec®, Novartis) led to significant changes in the treatment of chronic myeloid leukaemia (CML) patients. However, despite the impressive percentage of responding patients, some CML cases, particularly those in advanced phases of the disease, show primary resistance or relapse after the initial response. The second-generation BCR-ABL inhibitors nilotinib (Tasigna®, Novartis) and dasatinib (Sprycel®, Bristol-Myers Squibb) have shown significant activity in clinical trials in patients who failed imatinib therapy, but these agents are still incapable of inhibiting the T315I mutant of Bcr-Abl and present partial activity in advanced phases of CML. The acquired biological notions of the mechanisms of tyrosine kinase inhibitor (TKI) resistance has led to the development of new compounds, some of which have shown encouraging preliminary results in clinical trials, even against T315I mutants. In this paper we discuss the new emerging therapies which may overcome TKI resistance in CML patients.
A introdução do inibidor de tirosino quinase BCR-ABL mesilato de imatinibe (Glivec®, Novartis) levou a significantes mudanças no tratamento da LMC. Entretanto, a despeito de impressionante porcentagem de pacientes que respondem, alguns casos de LMC, particularmente em fases avançadas da doença mostram resistência primaria ou recidivas após terapêutica inicial. Inibidores de tirosino quinases de segunda geração como o nilotinibe (Tasigna®, Novartis) e o dasatinibe (Sprycel®, Bristol Myers Squibb) têm mostrado significante atividade nos estudos clínicos em paciente onde o imatinibe falhou. Porém, estes agentes não são capazes de inibir a mutação T315I do Bcr-Abl e apresentam atividade parcial em fases avançadas da LMC. As noções biológicas adquiridas sobre os mecanismos de resistência aos inibidores de TK levaram ao desenvolvimento de novos compostos alguns dos quais têm resultados preliminares encorajadores incluindo a mutação T315I. Neste trabalho nós discutimos os novos agentes emergentes e qual o potencial poderão atingir para ultrapassar a resistência aos inibidores de TK em pacientes com LMC.
Assuntos
Humanos , Resistência a Medicamentos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Proteínas Tirosina Quinases/antagonistas & inibidoresRESUMO
The Wilms' tumor gene WT1 is a reliable marker for minimal residual disease assessment in acute leukemia patients. The study was designed to demonstrate the potential use of WT1 to establish quality of remission in acute leukemia patients for early identification of patients at high risk of relapse. A prospective study based on a quantitative Real-Time PCR (TaqMan) assay in 562 peripheral blood samples collected from 82 acute leukemia patients at diagnosis and during follow-up was established. The evaluation of WT1 in peripheral blood samples after induction chemotherapy can distinguish the continuous complete remission patients from those who obtain only an "apparent" complete remission and who could relapse within a few months. WT1 helps identify patients at high risk of relapse soon after induction chemotherapy allowing post-induction therapy in high risk patients to be intensified.