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1.
Lancet Haematol ; 7(3): e238-e246, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31879230

RESUMO

BACKGROUND: Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies. METHODS: We did a multicentre, retrospective, cohort study in collaboration with the North American Shwachman-Diamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients. FINDINGS: We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 [56%] cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9-8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8-not reached) and 0·99 years (95% CI 0·2-2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1-39) for patients with leukaemia and 51% (29-68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia-including the two patients initially diagnosed with myelodysplastic who progressed- two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32-82; n=14) compared with 28% (95% CI 10-50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts. INTERPRETATION: Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome. FUNDING: National Institute of Health.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mieloide Aguda/mortalidade , Síndromes Mielodisplásicas/mortalidade , Síndrome de Shwachman-Diamond/mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Prognóstico , Estudos Retrospectivos , Síndrome de Shwachman-Diamond/patologia , Síndrome de Shwachman-Diamond/terapia , Taxa de Sobrevida , Adulto Jovem
2.
Blood Adv ; 3(20): 2911-2919, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31648312

RESUMO

Venetoclax is approved for older untreated acute myeloid leukemia (AML) patients. Venetoclax was available prior to approval off-label. We assessed our single-institution off-label experience with venetoclax/azacitidine, comparing outcomes with a clinical trial cohort that administered this regimen at the same institution. Thirty-three untreated AML patients unfit or unwilling to receive induction chemotherapy and prescribed venetoclax/azacitidine off-trial were retrospectively analyzed and compared with 33 patients who received the same therapy on trial. Outcomes were compared, and comparisons were made to a theoretical scenario in which off-trial patients received induction. Digital droplet polymerase chain reaction evaluated measurable residual disease (MRD). Off-trial venetoclax was attainable in nearly all patients for whom this was desired. The complete remission (CR)/CR with incomplete blood count recovery rate was 63.3% for off-trial patients who received treatment and 84.9% for trial patients (P = .081). The median overall survival for off-trial patients who received treatment was 381 days (95% confidence interval [CI], 174, not reached) vs 880 days (95% CI, 384, not reached) for trial patients (P = .041). Prior exposure to hypomethylating agents was associated with worse outcomes. Response rates with venetoclax/azacitidine were not inferior to a theoretical scenario in which patients received induction, and early death rates were less than expected with induction. MRD negativity was achievable. Newly diagnosed AML patients treated in a "real-world" scenario with off-trial venetoclax/azacitidine had inferior outcomes compared with patients treated in the setting of a clinical trial. Additionally, this therapy may be as effective, and less toxic, when compared with induction chemotherapy.

4.
Nat Commun ; 9(1): 2372, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29985391

RESUMO

Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Caderinas/fisiologia , Neoplasias de Cabeça e Pescoço/genética , Fosfoproteínas/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Caderinas/genética , Caderinas/metabolismo , Técnicas de Silenciamento de Genes , Células HEK293 , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Fatores de Transcrição
5.
Am J Hematol ; 93(7): 971-977, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29696694

RESUMO

BCR-ABL1-like B-lymphoblastic leukemia/lymphoma (BCR-ABL1-like B-ALL), also known as Philadelphia-like (Ph-like) ALL, is a neoplasm of B-lineage lymphoblasts characterized by a pattern of gene expression similar to that of B-ALL with the BCR-ABL1 translocation but lacking the BCR-ABL1 fusion protein. The diagnosis of BCR-ABL1-like B-ALL is associated with a high rate of relapse and poor clinical outcomes. In recognition of the difficulty in screening these leukemias for diagnostic workup, the 2016 update/revision to the World Health Organization (WHO) 2008 edition included BCR-ABL1-like B-ALL as a provisional entity. This review addresses the various clinical considerations and methodologies currently used in the pathologic diagnosis, subclassification, and molecular characterization of cases of BCR-ABL1-like B-ALL, with particular attention paid to emerging methods useful in identification of molecular lesions potentially amenable to targeted therapy.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Técnicas de Laboratório Clínico , Proteínas de Fusão bcr-abl , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/classificação , Translocação Genética
6.
Laryngoscope ; 128(4): 998-1001, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28771798

RESUMO

A 15-year-old boy was diagnosed with a cystic parotid mass, which was initially thought to be a first branchial cleft cyst. The mass was treated with antibiotics and fully resolved on examination and imaging. The mass returned, and a superficial parotidectomy was performed to remove the suspected branchial cleft cyst. Final pathology demonstrated a B-cell lymphoblastic lymphoma. Bilateral bone marrow biopsies and peripheral blood counts were negative for any malignancy. This case demonstrates a rare presentation of primary parotid B-cell lymphoblastic lymphoma that began as a fluctuating cystic parotid mass consistent in appearance with a first branchial cleft cyst. Laryngoscope, 128:998-1001, 2018.


Assuntos
Cistos/diagnóstico , Linfoma/diagnóstico , Imagem por Ressonância Magnética/métodos , Glândula Parótida/patologia , Neoplasias Parotídeas/diagnóstico , Adolescente , Biópsia por Agulha Fina , Diagnóstico Diferencial , Humanos , Masculino , Recidiva Local de Neoplasia/diagnóstico , Tomografia Computadorizada por Raios X
7.
Int J Pediatr Otorhinolaryngol ; 95: 97-100, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28576544

RESUMO

Cervical teratomas are relatively rare congenital tumors pathologically defined by their three germ cell layer composition. Classically they manifest as solid or mixed solid-cystic lesions. Purely cystic teratomas pose a diagnostic challenge due to their clinical and radiologic similarity to lymphatic vascular malformations. Sclerotherapy, rather than operative excision, may be offered as therapy. We present an unusual cystic neck mass to highlight this dilemma.


Assuntos
Pescoço/patologia , Teratoma/diagnóstico , Diagnóstico Diferencial , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Teratoma/cirurgia
8.
Am J Surg Pathol ; 41(3): 423-429, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27879517

RESUMO

The histologic differential diagnosis of pediatric and adult round cell tumors is vast and includes the recently recognized entity CIC-DUX4 fusion-positive round cell tumor. The diagnosis of CIC-DUX4 tumor can be suggested by light microscopic and immunohistochemical features, but currently, definitive diagnosis requires ancillary genetic testing such as conventional karyotyping, fluorescence in situ hybridization, or molecular methods. We sought to determine whether DUX4 expression would serve as a fusion-specific immunohistochemical marker distinguishing CIC-DUX4 tumor from potential histologic mimics. A cohort of CIC-DUX4 fusion-positive round cell tumors harboring t(4;19)(q35;q13) and t(10;19)(q26;q13) translocations was designed, with additional inclusion of a case with a translocation confirmed to involve the CIC gene without delineation of the partner. Round cell tumors with potentially overlapping histologic features were also collected. Staining with a monoclonal antibody raised against the C-terminus of the DUX4 protein was applied to all cases. DUX4 immunohistochemistry exhibited diffuse, crisp, strong nuclear staining in all CIC-DUX4 fusion-positive round cell tumors (5/5, 100% sensitivity), and exhibited negative staining in nuclei of all of the other tested round cell tumors, including 20 Ewing sarcomas, 1 Ewing-like sarcoma, 11 alveolar rhabdomyosarcomas, 9 embryonal rhabdomyosarcomas, 12 synovial sarcomas, 7 desmoplastic small round cell tumors, 3 malignant rhabdoid tumors, 9 neuroblastomas, and 4 clear cell sarcomas (0/76, 100% specificity). Thus, in our experience, DUX4 immunostaining distinguishes CIC-DUX4 tumors from other round cell mimics. We recommend its use when CIC-DUX4 fusion-positive round cell tumor enters the histologic differential diagnosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Sarcoma/diagnóstico , Adolescente , Criança , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Sarcoma/metabolismo , Sarcoma/patologia , Sensibilidade e Especificidade , Adulto Jovem
9.
Lung Cancer ; 95: 65-72, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27040854

RESUMO

Activating mutations in the epidermal growth factor receptor (EGFR) gene are exceedingly rare in small cell lung cancer (SCLC). We present two cases of SCLC harboring EGFR mutations, one in an 82 year-old male smoker with a combined SCLC and adenocarcinoma with a novel D855H point mutation in exon 21, and the second in a 68 year-old female never smoker with the L858R point mutation in exon 21. The cases, accompanied by a review of the literature, highlight the importance of integration of clinicopathologic considerations and adherence to recently promulgated Guideline recommendations for molecular testing in lung cancer.


Assuntos
Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação , Carcinoma de Pequenas Células do Pulmão/genética , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Códon , Terapia Combinada , Análise Mutacional de DNA , Evolução Fatal , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Masculino , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/terapia , Resultado do Tratamento
10.
Adv Exp Med Biol ; 720: 27-38, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21901616

RESUMO

The human oral squamous epithelium plays an important role in maintaining a barrier function against mechanical, physical, and pathological injury. However, the self-renewing cells residing on the basement membrane of the epithelium can give rise to oral squamous cell carcinomas (OSCC), now the sixth most common cancer in the developed world, which is still associated with poor prognosis. This is due, in part, to the limited availability of well-defined culture systems for studying oral epithelial cell biology, which could advance our understanding of the molecular basis of OSCC. Here, we describe methods to successfully isolate large cultures of human oral epithelial cells and fibroblasts from small pieces of donor tissues for use in techniques such as three-dimensional cultures and animal grafts to validate genes suspected of playing a role in OSCC development and progression. Finally, the use of isolated oral epithelial cells in generating iPS cells is discussed which holds promise in the field of oral regenerative medicine.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Separação Celular , Células Cultivadas , Células Epiteliais/fisiologia , Humanos , Queratinócitos/citologia , Mucosa Bucal/citologia , Células-Tronco/citologia
11.
J Surg Res ; 148(1): 83-9, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18570935

RESUMO

BACKGROUND: Translation initiation factor eIF4E unwinds long 5'-untranslated regions of certain tightly regulated mRNAs and, thereby, facilitates their translation into proteins. eIF4E has been shown to be overexpressed in a majority of solid tumors, including head and neck cancers. To exploit this dysregulation, a long 5'-untranslated region was spliced upstream of a thymidine kinase (Tk) gene to enhance translation of this "suicide" gene within cells overexpressing eIF4E. We investigated the efficacy of therapy with an adenovirus incorporating this novel suicide gene (Ad-HSV-UTk) following cytoreductive tumor surgery in improving disease-free and overall survival in a mouse soft-tissue metastasis model for head and neck squamous cell carcinoma. MATERIALS AND METHODS: SCC-7 (orally-derived mouse SCCa) cells were treated with Ad-HSV-Tk, Ad-HSV-UTk, Ad-null, or saline and characterized for eIF4E and Tk levels by Western blot analysis. Cytotoxicities for cells treated with Ad-HSV-Tk, Ad-HSV-UTk, or Ad-null were quantified by MTS assay. Mice bearing SCC-7-induced tumors received cytoreduction followed by Ad-HSV-UTk + ganciclovir (GCV) or control treatment and were followed for disease-free and overall survival. RESULTS: SCC-7 cells showed uniformly high levels of eIF4E but elevated Tk for Ad-HSV-Tk- and Ad-HSV-UTk-treated cells over Ad-null-treated cells. Cytotoxicities for Ad-HSV-Tk- and Ad-HSV-UTk-treated cells were, correspondingly, observed to be 100-fold more sensitive than Ad-null-treated cells to GCV treatment. Cytoreduced mice receiving Ad-HSV-UTk + GCV treatment showed significantly longer disease-free survival (P = 0.0045) than control arm mice. CONCLUSIONS: Ad-HSV-UTk suicide gene therapy prolonged disease-free survival in a mouse minimal residual soft-tissue head and neck squamous cell carcinoma metastasis model.


Assuntos
Carcinoma de Células Escamosas/terapia , Fator de Iniciação 4E em Eucariotos/genética , Terapia Genética/métodos , Neoplasias de Cabeça e Pescoço/terapia , Metástase Neoplásica/terapia , Animais , Linhagem Celular Tumoral , Intervalo Livre de Doença , Genes Transgênicos Suicidas , Vetores Genéticos , Camundongos , Camundongos Endogâmicos C3H , Neoplasias Experimentais
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