RESUMO
We recently described morgana as an essential protein able to regulate centrosome duplication and genomic stability, by inhibiting ROCK. Here we show that morgana (+/-) mice spontaneously develop a lethal myeloproliferative disease resembling human atypical chronic myeloid leukemia (aCML), preceded by ROCK hyperactivation, centrosome amplification, and cytogenetic abnormalities in the bone marrow (BM). Moreover, we found that morgana is underexpressed in the BM of patients affected by atypical CML, a disorder of poorly understood molecular basis, characterized by nonrecurrent cytogenetic abnormalities. Morgana is also underexpressed in the BM of a portion of patients affected by Philadelphia-positive CML (Ph(+) CML) caused by the BCR-ABL oncogene, and in this condition, morgana underexpression predicts a worse response to imatinib, the standard treatment for Ph(+) CML. Thus, morgana acts as an oncosuppressor with different modalities: (1) Morgana underexpression induces centrosome amplification and cytogenetic abnormalities, and (2) in Ph(+) CML, it synergizes with BCR-ABL signaling, reducing the efficacy of imatinib treatment. Importantly, ROCK inhibition in the BM of patients underexpressing morgana restored the efficacy of imatinib to induce apoptosis, suggesting that ROCK inhibitors, combined with imatinib treatment, can overcome suboptimal responses in patients in which morgana is underexpressed.
Assuntos
Benzamidas/farmacologia , Proteínas de Transporte/fisiologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Cromossomo Filadélfia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Apoptose , Western Blotting , Medula Óssea/metabolismo , Medula Óssea/patologia , Proliferação de Células , Citometria de Fluxo , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Técnicas Imunoenzimáticas , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismoRESUMO
Oral dysontogenic cysts result from defective embryonic development. Among them teratoid cysts are the most unusual presentation and may be lined by gastric, intestinal, respiratory, squamous, ciliated epithelium or even pancreatic structures. Teratoid cysts containing respiratory and gastrointestinal epithelium have typically been called choristomas. This article describes a 15-year-old boy presenting a choristoma involving both the floor of the mouth and the anterior tongue and characterized by the presence of squamous epithelium with skin adnexa, gastric and respiratory epithelium.
Assuntos
Coristoma/diagnóstico , Mucosa Gástrica/patologia , Doenças da Boca/diagnóstico , Soalho Bucal/patologia , Neoplasias Bucais/diagnóstico , Mucosa Respiratória/patologia , Teratoma/diagnóstico , Doenças da Língua/diagnóstico , Neoplasias da Língua/diagnóstico , Adolescente , Biópsia por Agulha Fina , Diagnóstico Diferencial , Epitélio/patologia , Seguimentos , Humanos , Masculino , Pele/patologiaRESUMO
Breast carcinoma is the most prevalent cancer among women globally. It has variable clinical courses depending on the stage and clinical-biological features. This case report describes a 56-year-old female with invasive breast cancer without estrogen or progesterone receptor expression, with apocrine differentiation, and with no germline variants in the BRCA1 and BRCA2 genes. Throughout the clinical course, the patient exhibited discordant results for HER2 in immunohistochemistry and in situ hybridization. During the second relapse, the disease displayed apocrine microscopic features. The tumor underwent analysis for the androgen receptor, GCDFP-15, RNA-seq, and whole-genome sequencing (WGS) to identify the breast cancer subtype and to characterize the cancer genome. Our bioinformatic analysis revealed 20,323 somatic SNV/Indels, including five mutations in cancer-related genes that are believed to be responsible for the tumor's development. Two of these mutations were found in the PIK3CA and TP53 genes. Furthermore, the tumor tissue exhibited large copy number alterations to the chromosomes, which could impact gene expression through complex mechanisms and contribute to the tumor phenotype. Clustering algorithms applied on RNA-sequencing data categorized this cancer as a HER2+ subtype. The second-line capecitabine chemotherapy treatment is ongoing, and the patient is responding well. Bioinformatic results support the current treatment decision and open the way to further treatments.
RESUMO
OBJECTIVE: 'Field cancerization' is an accepted model for oral carcinogenesis. So far, genetically altered fields have been just reported in the presence of carcinomas. This study assessed the distant mirror fields (MFs) of oral precancer by DNA high-resolution flow cytometry (hr DNA-FCM) and array-Comparative Genomic Hybridization (a-CGH). METHODS: Five leukoplakias without dysplasia (OLs), seven dysplastic leukoplakias (DOLs), and 12 corresponding visually normal and non-dysplastic MFs were analyzed. DNA aneuploidy (DNA Index, DI ≠ 1) was detected by hr DNA-FCM on DAPI stained nuclei suspensions. The epithelial DNA aneuploid subclones were FCM-sorted to obtain genomic DNA for a-CGH. RESULTS: Mirror fields, OLs, and DOLs showed increasing prevalence of DNA aneuploidy of, respectively, 8%, 20%, and 57%. The average number of chromosome aberrations (Ch-Abs) was 2.8 in MFs, 3 in OLs, and 10.6 in DOLs. MFs relative to OLs and DOLs had average numbers of Ch-Abs, respectively, of 1.8 and 3.6. Ch-Abs were also observed in DNA diploid sublines, and often the same aberrations were observed in both MFs and corresponding OLs/DOLs. CONCLUSION: DNA aneuploidy and Ch-Abs in MFs, the last ones being mainly gains, indicate an early onset of field effect in oral carcinogenesis.
Assuntos
Hibridização Genômica Comparativa/métodos , DNA de Neoplasias/análise , Citometria de Fluxo/métodos , Neoplasias Bucais/genética , Lesões Pré-Cancerosas/genética , Adulto , Idoso , Aneuploidia , Núcleo Celular/ultraestrutura , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Instabilidade Cromossômica/genética , Aberrações Cromossômicas/classificação , Diploide , Feminino , Corantes Fluorescentes , Humanos , Indóis , Leucoplasia Oral/genética , Leucoplasia Oral/patologia , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/citologia , Neoplasias Bucais/patologia , Projetos Piloto , Lesões Pré-Cancerosas/patologiaRESUMO
BACKGROUND: Oral verrucous carcinomas (OVCs) are characterized by better prognosis than oral squamous cell carcinomas (OSCCs). Because chromosomal instability (CIN) in solid tumors is indicative of prognosis, this study investigated whether OVCs and OSCCs were characterized by differences in CIN biomarkers. METHODS: Fresh or frozen multiple tissue samples were submitted to high-resolution DNA flow cytometry (hr DNA-FCM). RESULTS: DNA aneuploid sublines were detected in 6 of 9 OVCs (66.7%) and in 20 of 25 OSCCs (80.0%). Multiple DNA aneuploid sublines were observed, respectively, in 2 of 6 (33.3%) DNA aneuploid OVCs and in 14 of 20 (70%) DNA aneuploid OSCCs (P = .163). OVCs were mainly characterized by DNA Index (DI) values in the near-diploid region (DI≠1 and DI < 1.4), whereas aneuploid OSCCs carried most frequently multiple aneuploid sublines with high DI values (DI ≥ 1.4). DNA near-diploid and high aneuploid sublines were, respectively, 87.5% and 12.5% for the OVCs versus 30% and 70% for the OSCCs (P = .004). CONCLUSIONS: Present data suggest that OVCs are characterized by a lower degree of CIN and tumor heterogeneity than OSCCs, such that they appear as "frozen" in an early stage of DNA near-diploid aneuploidy, as previously observed for oral preneoplastic lesions. These DI characteristics, which can easily be obtained by hr DNA-FCM, appear to reflect the well-known differences in aggressiveness and prognosis of OVCs and OSCCs.
Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma Verrucoso/genética , Instabilidade Cromossômica , Idoso , Aneuploidia , DNA de Neoplasias/genética , Feminino , Citometria de Fluxo , Humanos , MasculinoRESUMO
Association between thymoma and pure red cell aplasia is already well-documented in literature whereas acquired amegakaryocytic thrombocytopenia is rarely reported. In this case, even with the addition of eltrombopag to standard immunosuppression, the cytopenias did not improve, probably due to the lack of surgical resection of the tumor.
RESUMO
Malignant fibrous histiocytoma (MFH) is a pleomorphic sarcoma, occurring most frequently in the deep soft tissues of the extremities, and it is most frequently seen in elderly patients. A primary MFH of the diaphragm is very rare, and to the best of our knowledge, a multi-phased spiral CT appearance of this tumour has not been previously reported. In this report, we describe the clinical and multi-phase CT features of a primary MFH of the diaphragm.
Assuntos
Diafragma/patologia , Histiocitoma Fibroso Maligno/diagnóstico por imagem , Neoplasias Musculares/diagnóstico por imagem , Idoso , Diafragma/diagnóstico por imagem , Feminino , Histiocitoma Fibroso Maligno/complicações , Humanos , Região Lombossacral , Neoplasias Musculares/complicações , Dor/etiologia , Tomografia Computadorizada EspiralRESUMO
The identification of cystic lesions within the retroperitoneal space is a rare event that poses clinicians the challenge of a difficult diagnosis and disease management. Retroperitoneal cystic lesions account for a group of lesions that range from common benign lesions (e.g., lymphoceles developing as a surgical complication) to rare aggressive malignant neoplasms. Currently, in the majority of cases, image-guided procedures allow for a pathological diagnosis to be achieved in these challenging lesions, thus offering the chance of an appropriate treatment; however, the overall clinical assessment of retroperitoneal cysts is highly demanding. The present study reports the management of a representative clinical case, presenting with a voluminous cystic mass able to dislocate cave vein, whose diagnosis was preceded by a deep vein thrombosis. Computed tomography-scan and ultrasound guided percutaneous drainage were performed to achieve the diagnosis. Following the discussion of the current case report, a review of the pathological and radiological characteristics of retroperitoneal cystic lesions is presented.
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Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder with either indolent or aggressive clinical course. Current treatment regiments have significantly improved the overall outcomes even if higher risk subgroups - those harboring TP53 mutations or deletions of the short arm of chromosome 17 (del17p) - remain highly challenging. In the present work, we identified USP7, a known de-ubiquitinase with multiple roles in cellular homeostasis, as a potential therapeutic target in CLL. We demonstrated that in primary CLL samples and in CLL cell lines USP7 is: i) over-expressed through a mechanism involving miR-338-3p and miR-181b deregulation; ii) functionally activated by Casein Kinase 2 (CK2), an upstream interactor known to be deregulated in CLL; iii) effectively targeted by the USP7 inhibitor P5091. Treatment of primary CLL samples and cell lines with P5091 induces cell growth arrest and apoptosis, through the restoration of PTEN nuclear pool, both in TP53-wild type and -null environment. Importantly, PTEN acts as the main tumor suppressive mediator along the USP7-PTEN axis in a p53 dispensable manner. In conclusion, we propose USP7 as a new druggable target in CLL.
Assuntos
Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/genética , PTEN Fosfo-Hidrolase/genética , Peptidase 7 Específica de Ubiquitina/genética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Deleção de Genes , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Modelos Biológicos , Mutação , PTEN Fosfo-Hidrolase/metabolismo , Transporte Proteico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Peptidase 7 Específica de Ubiquitina/metabolismo , Regulação para CimaRESUMO
Tumor suppressor function can be modulated by subtle variation of expression levels, proper cellular compartmentalization and post-translational modifications, such as phosphorylation, acetylation and sumoylation. The non-genomic loss of function of tumor suppressors offers a challenging therapeutic opportunity. The reactivation of a tumor suppressor could indeed promote selective apoptosis of cancer cells without affecting normal cells. The identification of mechanisms that affect tumor suppressor functions is therefore essential. In this work, we show that BCR-ABL promotes the accumulation of the NFKBIA gene product, IκBα, in the cytosol through physical interaction and stabilization of the protein. Furthermore, BCR-ABL/IκBα complex acts as a scaffold protein favoring p53 nuclear exclusion. We therefore identify a novel BCR-ABL/IκBα/p53 network, whereby BCR-ABL functionally inactivates a key tumor suppressor.
Assuntos
Proteínas de Fusão bcr-abl/metabolismo , Proteínas I-kappa B/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Transporte Ativo do Núcleo Celular , Citosol/metabolismo , Proteínas de Fusão bcr-abl/genética , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Proteínas I-kappa B/genética , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Complexos Multiproteicos , Inibidor de NF-kappaB alfa , Transdução de Sinais , Fatores de Tempo , Transfecção , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: Thymic epithelial tumors include several entities with different biologic behavior. Chemotherapy is indicated in advanced disease, but limited data exist on gene expression correlation with the response to chemotherapeutic agents. PATIENTS AND METHODS: A series of 69 thymic neoplasms (7 A-, 6 AB-, 6 B1-, 10 B2-, 14 B3-thymomas, 22 carcinomas and 4 combined tumors) was collected to assess gene expression of thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), ribonucleotide reductase subunit 1 (RRM1), topoisomerase 2α (TOP2A) and mTOR. RESULTS: A strong linear correlation between TS gene and protein expression was observed (P<0.0001, R=0.40). TS expression was significantly lower in pure A-thymomas and thymic carcinomas (P<0.0001) and progressively decreasing from B1-type to thymic carcinomas (B1>B2>B3>C; P<0.0001). RRM1 and TOP2A mRNA expression levels were significantly correlated with TS levels (both P=0.03) with a similar trend of expression among histotypes. RRM1 and TOP2A high levels were significantly correlated with high TS (P=0.03) and low tumor stages (I-II) (P<0.0001 and P<0.01, respectively). No relevant changes of ERCC1 and mTOR were detected. CONCLUSIONS: Low TS and, to a minor extent, RRM1 and TOP2A expression were detected in aggressive thymic tumors. These findings should be prospectively considered in selecting the most appropriate chemotherapy.
Assuntos
Reparo do DNA/genética , Timidilato Sintase/metabolismo , Timoma/patologia , Neoplasias do Timo/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Transformação Celular Neoplásica , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endonucleases/genética , Endonucleases/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose , RNA Mensageiro/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Timidilato Sintase/genética , Timoma/tratamento farmacológico , Timoma/enzimologia , Timoma/genética , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/enzimologia , Neoplasias do Timo/genética , Adulto Jovem , Fator ral de Troca do Nucleotídeo Guanina/genética , Fator ral de Troca do Nucleotídeo Guanina/metabolismoRESUMO
Thymic carcinoma (primary carcinoma of the thymic epithelium; type C thymoma) is a rare malignancy. It usually presents in middle-aged to elderly patients and can exhibit a wide variety of morphologic appearances. Thymic basaloid carcinoma (thymic BC) is a particularly rare subtype, with less than 20 cases published in the English literature, mostly in the form of individual case reports. In this study, we present the clinicopathologic and immunohistochemical features of 12 new cases of thymic BC. There were 10 (83%) men and 2 (17%) women. Ages at the time of initial diagnosis ranged from 34 to 77 years (mean 55 y). The 2 most common manners of presentation were dyspnea on exertion (3 patients) and as an incidental finding on radiographic imaging (2 patients). Tumors ranged in size from 4.4 to 17 cm (mean 10.1 cm). One of 12 cases (8.3%) was associated with a multilocular thymic cyst. Immunohistochemistry was performed in 8 cases. Pan-cytokeratin was positive in all cases. CD117 (c-kit) was positive in 6 of 8 cases (75%), p63 was positive in 7 of 8 cases (88%), p53 was positive in 7 of 8 cases (88%), ranging from <10% to 90%, CD5 was focally positive in 3 of 8 cases (38%), collagen type IV was positive in 4 of 8 cases (50%), and proliferative index, as estimated by Ki67, ranged from <1% to approximately 15%. In 1 of 2 cases with sarcomatoid differentiation, Ki67 was greater than 80% in the sarcomatoid area. Cases were negative for thyroid transcription factor-1 (0 of 8), S-100 (0 of 7), and synaptophysin (0 of 7). Long-term data was available in 8 patients with an average follow-up of 30 months. Five patients died of their disease at an average of 34 months from the time of diagnosis. Of the remaining 3 patients, 1 had a stable recurrence and died at 4 years from unrelated causes, and 2 were alive without the evidence of disease at 12 and 7 months, respectively. Thymic BC, although previously regarded as a low-grade neoplasm, has shown that it is capable of aggressive behavior and significant mortality. In this paper, we review the pertinent literature and discuss the possible relationship of thymic BC with thymic adenoid cystic carcinoma, as well as BCs and adenoid cystic carcinomas at other sites.
Assuntos
Carcinoma Adenoide Cístico/patologia , Carcinoma de Células de Transição/patologia , Neoplasias do Timo/patologia , Adulto , Idoso , Carcinoma Adenoide Cístico/metabolismo , Carcinoma de Células de Transição/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias do Timo/metabolismoRESUMO
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 SecundáriaRESUMO
We report the case of a 25-year-old woman with a chance detection at x-ray of a well-defined mass in the right upper lobe during a medical examination. The patient suffered from a modest flu syndrome, with cough and fever. She was a current smoker. CT scan showed a homogeneous well-defined perihilar mass without calcifications, located in the right upper lobe and fully surrounded by aerated parenchyma. A right upper lobectomy with mediastinal lymph node sampling was performed. A pathologic diagnosis of well-differentiated fetal adenocarcinoma of the lung was made and staged as T2N0. Few cases of this type of malignancy have been reported in literature.
Assuntos
Adenocarcinoma/patologia , Neoplasias Pulmonares/patologia , Blastoma Pulmonar/patologia , Adulto , Diferenciação Celular , Feminino , Humanos , PneumonectomiaRESUMO
BACKGROUND: The authors investigated the efficacy and safety of the histone deacetylase inhibitors valproic acid (VPA) and all-trans retinoic acid (ATRA) as differentiation agents in a cohort of older, poor-risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). METHODS: Twenty older patients with recurrent or refractory AML or MDS were treated in a Phase II protocol with sequential VPA and ATRA therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve the serum concentration of 45-100 microg/mL. ATRA was added at 45 mg/square meters (sm) per day when VPA reached the target serum concentration. Only patients treated continuously for > or = 2 months were considered evaluable. RESULTS: Hematologic improvement, according to World Health Organization criteria, was observed in 6 of 20 patients enrolled in the protocol but in 6 of 11 considered evaluable. In five patients, a major platelet response was observed, achieving platelet transfusion independence. Three of these five patients also exhibited a minor erythroid response. A sixth patient showed both a minor erythroid response and a platelet response. The median duration of response was 189 days (range, 63-550 days). No significant reduction in the blast count was observed. Grade 3 neurocortical toxicity was observed in four patients. Severe bone pain was experienced by 4 patients (2 Grade 4 and 2 Grade 3) and was associated with an increase in the peripheral blast cell count. Treatment with ATRA did not modify the response observed with VPA alone. CONCLUSIONS: Differentiation therapy with VPA was of clinical benefit in approximately 30% of elderly patients with AML and MDS of the refractory anemia with excess of blast type with unfavorable prognostic features. A striking platelet transfusion independence lasting several months may be obtained in some patients, reducing the burden of palliative care and improving the quality of life.