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1.
Genes Chromosomes Cancer ; 63(1): e23211, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37897298

RESUMEN

High-grade B-cell lymphoma (HGBL)/diffuse large B-cell lymphoma (DLBCL) with rearrangements (R) in MYC and BCL2 and/or BCL6 are correlated with poor prognosis. Little is known about the impact of other genetic alterations (gain (G) or amplification (A)) of these genes. The aim of the study was to investigate whether we can identify new prognostic subgroups. Fluorescence in situ hybridization (FISH) results from 169 HGBL/DLBCL were retrospectively categorized into: (1) concurrent MYC-R and BCL2-R and/or BCL6-R-samples with MYC-R and BCL2-R (+/- BCL6-R); n = 21, and HGBL/DLBCL with MYC-R and BCL6-R; n = 11; (2) concurrent R and G/A in MYC and BCL2 and/or BCL6 called "alternative HGBL/DLBCL"-samples with (n = 16) or without (n = 6) BCL2 involvement; (3) BCL2 and/or BCL6 alterations without MYC involvement (n = 35); (4) concurrent G/A in MYC and BCL2 and/or BCL6 without R (n = 25); and (5) "No alterations" (n = 55). Patients with HGBL/DLBCL-MYC/BCL2 and "alternative" HGBL/DLBCL (with BCL2 involvement) had significantly worse survival rates compared to the "no alterations" group. G/A of these genes in the absence of rearrangements did not show any prognostic significance. HGBL/DLBCL with MYC-R and BCL6-R without BCL2 involvement showed a better survival rate compared to HGBL/DLBCL-MYC/BCL2. According to immunohistochemistry, "double/triple" expression (DEL/TEL) did not show a significantly worse outcome compared to absent DEL/TEL. This study highlights the continued value of FISH assessment of MYC, BCL2, and BCL6 in the initial evaluation of HGBL/DLBCL with different survival rates between several genetic subgroups.


Asunto(s)
Linfoma de Células B Grandes Difuso , Proteínas Proto-Oncogénicas c-bcl-2 , Humanos , Reordenamiento Génico , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-myc/genética , Estudios Retrospectivos
2.
Int J Gynecol Pathol ; 43(3): 215-220, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-37922949

RESUMEN

Fibroepithelial stromal polyps (FSPs) are benign mesenchymal lesions occurring in the vulvovaginal region. Following the identification of loss of Retinoblastoma 1 (RB1) on immunohistochemical staining in routine practice, we stained a series of FSPs and performed additional fluorescence in situ hybridization (FISH) and copy number variation (CNV) sequencing to detect losses/deletions in the Retinoblastoma transcriptional corepressor 1 (RB1) gene. Fifteen FSP cases were stained for RB1, and subsequently, 9 cases were examined by FISH to detect a loss of RB1 (13q). Next, CNV sequencing was performed to assess genomic alterations. The mean age of the patients was 50 years. Loss of RB1 expression on immunohistochemistry was seen in 13 cases, and heterogeneous RB1 staining in the remaining 2 cases. FISH showed deletion of RB1 in all of the cases. CNV sequencing failed in almost all cases due to a low tumor content. Based on our findings, we hypothesize that FSPs are part of a spectrum of genetically related lesions, namely the 13q/RB1 family of tumors (which includes pleomorphic fibromas and spindle cell/pleomorphic lipomas). Due to the clinical, morphologic, and molecular overlap, we suggest that FSPs are pleomorphic fibromas occurring in the specialized stroma of the genital region.

3.
Acta Chir Belg ; 123(6): 695-698, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36069512

RESUMEN

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) masquerading as a recurrent inguinal hernia is rare. We report the case of a 73-year-old male patient who presented with a symptomatic bulge in his left groin. Medical history revealed bilateral preperitoneal inguinal hernia repair, osteoporosis and atrial fibrillation. The patient's further history was not significant. METHODS: Sonography revealed recurrence of an indirect inguinal hernia (4.5 cm × 2.3 cm) on the left, with bilateral subcutaneous lymph nodes that were deemed unremarkable. We planned an elective left-sided anterior inguinal repair. Apixaban was stopped two days prior to surgery. RESULTS: During surgery we identified the bulge as a lump attached to the spermatic cord. No hernial sac was present. Together with the consulting urologist, we concluded a possible malignant etiology and performed an orchiectomy along with resection of the lump. CONCLUSION: Microscopic and immunohistochemical analysis revealed a DLBCL with non-germinal center phenotype and c-MYC rearrangement. Further staging confirmed stage IE disease with extranodal paratesticular involvement. The patient was subsequently treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, prednisone and showed complete metabolic remission after two cycles. This case illustrates the broad differential diagnosis of inguinal swelling and (para)testicular tumors.


Asunto(s)
Hernia Inguinal , Linfoma de Células B Grandes Difuso , Neoplasias Testiculares , Masculino , Humanos , Anciano , Hernia Inguinal/diagnóstico , Hernia Inguinal/cirugía , Ciclofosfamida , Ganglios Linfáticos/patología , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/patología
4.
Int J Mol Sci ; 23(7)2022 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-35409398

RESUMEN

Mosaic RASopathies are a molecularly heterogeneous group of (neuro)cutaneous syndromes with high phenotypical variability. Postzygotic variants in KRAS have been described in oculoectodermal syndrome (OES), encephalocraniocutaneous lipomatosis (ECCL) and epidermal nevus syndrome (ENS). This study confirms the continuum of mosaic neurocutaneous RASopathies showing codon 146 KRAS variants in an individual with OES and, for the first time, in an individual with (isolated) epidermal nevus. The presence of a nevus psiloliparus in individuals with OES indicates that this finding is not specific for ECCL and highlights the phenotypical overlap between ECCL and OES. The presence of the somatic KRAS variant in the nevus psiloliparus resolves the underlying molecular etiology of this fatty-tissue nevus. In addition, this finding refutes the theory of non-allelic twin-spotting as an underlying hypothesis to explain the concurrent presence of two different mosaicisms in one individual. The identification of codon 146 KRAS variants in isolated epidermal nevus introduces a new hot spot for this condition, which is useful for increasing molecular genetic testing using targeted gene sequencing panels.


Asunto(s)
Hamartoma , Nevo , Codón/genética , Quiste Dermoide , Displasia Ectodérmica , Oftalmopatías , Humanos , Lipomatosis , Síndromes Neurocutáneos , Nevo/genética , Proteínas Proto-Oncogénicas p21(ras)/genética
5.
Genes Chromosomes Cancer ; 55(5): 428-41, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26850007

RESUMEN

The recurrent 9p24.1 aberrations in lymphoid malignancies potentially involving four cancer-related and druggable genes (JAK2, CD274/PDL1, PDCD1LG2/PDL2, and KDM4C/JMJD2Cl) are incompletely characterized. To gain more insight into the anatomy of these abnormalities, at first we studied 9p24.1 alterations in 18 leukemia/lymphoma cases using cytogenetic and molecular techniques. The aberrations comprised structural (nine cases) and numerical (nine cases) alterations. The former lesions were heterogeneous but shared a common breakpoint region of 200 kb downstream of JAK2. The rearrangements predominantly targeted the PDL locus. We have identified five potential partner genes of PDL1/2: PHACTR4 (1p34), N4BP2 (4p14), EEF1A1 (6q13), JAK2 (9p24.1), and IGL (22q11). Interestingly, the cryptic JAK2-PDL1 rearrangement was generated by a microdeletion spanning the 3'JAK2-5'PDL1 region. JAK2 was additionally involved in a cytogenetically cryptic IGH-mediated t(9;14)(p24.1;q32) found in two patients. This rare but likely underestimated rearrangement highlights the essential role of JAK2 in B-cell neoplasms. Cases with amplification of 9p24.1 were diagnosed as primary mediastinal B-cell lymphoma (five cases) and T-cell lymphoma (four cases). The smallest amplified 9p24.1 region was restricted to the JAK2-PDL1/2-RANBP6 interval. In the next step, we screened 200 cases of classical Hodgkin lymphoma by interphase FISH and identified PDL1/2 rearrangement (CIITA- and IGH-negative) in four cases (2%), what is a novel finding. Forty (25%) cases revealed high level amplification of 9p24.1, including four cases with a selective amplification of PDL1/2. Altogether, the majority of 9p24.1 rearrangements occurring in lymphoid malignancies seem to target the programmed death-1 ligands, what potentiates the therapeutic activity of PD-1 blockade in these tumors. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Antígeno B7-H1/genética , Janus Quinasa 2/genética , Linfoma/genética , Mutación , Bandeo Cromosómico , Perfilación de la Expresión Génica , Humanos , Cariotipificación
6.
Haematologica ; 100(7): 893-7, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25934766

RESUMEN

The JAK2 V617F mutation, the thrombopoietin receptor MPL W515K/L mutation and calreticulin (CALR) mutations are mutually exclusive in essential thrombocythemia and support a novel molecular categorization of essential thrombocythemia. CALR mutations account for approximately 30% of cases of essential thrombocythemia. In a retrospective study, we examined the frequency of MPL and CALR mutations in JAK2 V617F-negative cases of essential thrombocythemia (n=103). In addition, we compared the clinical phenotype and outcome of CALR mutant cases of essential thrombocythemia with a cohort of JAK2 V617F-positive essential thrombocythemia (n=57). CALR-positive cases represented 63.7% of double-negative cases of essential thrombocythemia, and most carried CALR type 1 or type 2 indels. However, we also identified one patient who was positive for both the JAK2 V617F and the CALR mutations. This study revealed that CALR mutant essential thrombocythemia is associated with younger age, higher platelet counts, lower erythrocyte counts, leukocyte counts, hemoglobin, and hematocrit, and increased risk of progression to myelofibrosis in comparison with JAK2 V617F-positive essential thrombocythemia. Analysis of the CALR mutant group according to indel type showed that CALR type 1 deletion is strongly associated with male gender. CALR mutant patients had a better overall survival than JAK2 V617F-positive patients, in particular patients of age 60 years or younger. In conclusion, this study in a Belgian cohort of patients supports and extends the growing body of evidence that CALR mutant cases of essential thrombocythemia are phenotypically distinct from JAK2 V617F-positive cases, with regards to clinical and hematologic presentation as well as overall survival.


Asunto(s)
Calreticulina/genética , Janus Quinasa 2/genética , Leucemia Mieloide Aguda/genética , Mutación , Mielofibrosis Primaria/genética , Trombocitemia Esencial/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Fenotipo , Recuento de Plaquetas , Mielofibrosis Primaria/etiología , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/patología , Receptores de Trombopoyetina/genética , Estudios Retrospectivos , Factores Sexuales , Análisis de Supervivencia , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/mortalidad , Trombocitemia Esencial/patología
7.
Haematologica ; 99(4): 656-63, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24162791

RESUMEN

Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this study, we compared the outcome of immunosuppressive therapy using horse antithymocyte globulin (n=46) with that using rabbit antithymocyte globulin (n=49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse antithymocyte globulin and 53% for rabbit antithymocyte globulin (P=0.04). The inferior response in the rabbit antithymocyte globulin group resulted in lower 4-year transplantation-free (69% versus 46%; P=0.003) and failure-free (58% versus 48%; P=0.04) survival rates in this group compared with those in the horse antithymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% versus 85%; P=ns). The cumulative incidence of relapse (15% versus 9%; P=ns) and clonal evolution (12% versus 4%; P=ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit antithymocyte globulin is inferior to that of horse antithymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: NCT00662090).


Asunto(s)
Suero Antilinfocítico/uso terapéutico , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Pancitopenia/tratamiento farmacológico , Adolescente , Animales , Suero Antilinfocítico/administración & dosificación , Niño , Preescolar , Femenino , Caballos , Humanos , Inmunosupresores/administración & dosificación , Lactante , Masculino , Pancitopenia/diagnóstico , Conejos , Recurrencia , Factores de Riesgo , Resultado del Tratamiento
8.
Am J Surg Pathol ; 48(10): 1277-1283, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-38912716

RESUMEN

Poorly differentiated thyroid carcinoma (PDTC) is a rare malignancy, representing ~1% of all thyroid tumors. It is characterized by high-grade histologic features without the anaplastic characteristics observed in anaplastic thyroid carcinoma. Although rare in children and young adults, there is emerging evidence of clinical and genetic differences with PDTC in adults. We present a case of a 19-year-old female with a right thyroid lobe nodule classified as an EU-TIRADS 5 lesion. Subsequent FNAC showed a cellular aspirate of solitary cells and scant microfollicles with variable nuclear irregularities, which was designated a Bethesda class IV lesion. Thyroidectomy revealed histopathological features consistent with PDTC, including solid/trabecular growth, increased mitotic activity, central necrosis, and extensive vascular invasion. Molecular analysis identified germline and somatic DICER1 mutations in the absence of other established driver mutations of PDTC. This case report describes the fourth reported patient with a PDTC and germline DICER1 mutation. Our findings contribute to a limited body of literature on pediatric/young adult PDTC cases and highlight the pivotal role of DICER1 mutations. Emerging evidence suggests that pediatric PDTC may exhibit unique clinical and genetic characteristics, prompting further research into its molecular profile.


Asunto(s)
ARN Helicasas DEAD-box , Ribonucleasa III , Neoplasias de la Tiroides , Humanos , Ribonucleasa III/genética , Femenino , ARN Helicasas DEAD-box/genética , Adulto Joven , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/cirugía , Mutación de Línea Germinal , Tiroidectomía , Predisposición Genética a la Enfermedad , Análisis Mutacional de ADN , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Fenotipo , Diferenciación Celular
9.
Blood ; 117(15): 4056-64, 2011 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-21325169

RESUMEN

The genetics of classical Hodgkin lymphoma (cHL) is poorly understood. The finding of a JAK2-involving t(4;9)(q21;p24) in 1 case of cHL prompted us to characterize this translocation on a molecular level and to determine the prevalence of JAK2 rearrangements in cHL. We showed that the t(4;9)(q21;p24) leads to a novel SEC31A-JAK2 fusion. Screening of 131 cHL cases identified 1 additional case with SEC31A-JAK2 and 2 additional cases with rearrangements involving JAK2. We demonstrated that SEC31A-JAK2 is oncogenic in vitro and acts as a constitutively activated tyrosine kinase that is sensitive to JAK inhibitors. In vivo, SEC31A-JAK2 was found to induce a T-lymphoblastic lymphoma or myeloid phenotype in a murine bone marrow transplantation model. Altogether, we identified SEC31A-JAK2 as a chromosomal aberration characteristic for cHL and provide evidence that JAK2 rearrangements occur in a minority of cHL cases. Given the proven oncogenic potential of this novel fusion, our studies provide new insights into the pathogenesis of cHL and indicate that in at least some cases, constitutive activation of the JAK/STAT pathway is caused by JAK2 rearrangements. The finding that SEC31A-JAK2 responds to JAK inhibitors indicates that patients with cHL and JAK2 rearrangements may benefit from targeted therapies.


Asunto(s)
Reordenamiento Génico/genética , Enfermedad de Hodgkin/genética , Janus Quinasa 2/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Transporte Vesicular/genética , Adulto , Anciano de 80 o más Años , Animales , Trasplante de Médula Ósea , Cromosomas Humanos Par 4 , Cromosomas Humanos Par 9 , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Células HEK293 , Enfermedad de Hodgkin/epidemiología , Humanos , Masculino , Ratones , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prevalencia , Proteínas Tirosina Quinasas/metabolismo , Translocación Genética , Adulto Joven
10.
Artículo en Inglés | MEDLINE | ID: mdl-38064892

RESUMEN

Summary: Primary hyperparathyroidism most commonly presents with hypercalcaemia. Rarely, parathyroid apoplexy or haemorrhage mimicking a thyroid bleeding cyst is the first presentation of a parathyroid adenoma. A woman presented with a sudden-onset painful 'goitre'. Ultrasound showed a cystic nodule located posterior to rather than in the right thyroid lobe, suggesting parathyroid adenoma bleeding. Biochemistry showed mild primary hyperparathyroidism. 99mTc-pertechnetate/sestamibi showed no uptake in the nodule, which was interpreted as a cold thyroid nodule. 18F-fluorocholine PET/CT showed uptake in the nodule, suggestive of a parathyroid adenoma. Persistent mild primary hyperparathyroidism complicated by nephrolithiasis and osteopenia favoured parathyroidectomy over a wait-and-see approach. The patient was referred for parathyroidectomy along with right thyroid lobectomy. Pathology showed an adenoma, with an eccentrically located cystic structure filled with red blood cells surrounded by a thickened fibrous capsule. In conclusion, cervical pain/haemorrhage with hypercalcaemia points to the diagnosis of parathyroid apoplexy, mimicking a thyroid bleeding cyst. Workup with ultrasound and, if available, 18F-choline PET/CT allows for timely surgery, minimizing the risk of recurrent and severe bleeding. Learning points: A bleeding cyst may be located posterior to rather than in the thyroid, suggesting a parathyroid haemorrhage. Neck pain and/or haemorrhage along with primary hyperparathyroidism point to parathyroid apoplexy. A two-step presentation has been described, with a first phase of local symptoms to be followed by visible and possibly life-threatening compressing bleeding. Therefore, an expedited workup is needed, allowing for timely surgery.

11.
Diagn Pathol ; 18(1): 52, 2023 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-37098615

RESUMEN

Breast-implant associated (BIA) lymphoma is an infrequent type of cancer occurring in the fluid and fibrous capsule around a textured breast implant. Recently, both the 2022 WHO 5th edition classification of Haematological tumours (WHO HAEM5) and 2022 International Consensus Classification of Mature Lymphoid Neoplasms (22ICC), recognized breast implant-associated Anaplastic Large Cell Lymphoma (BIA-ALCL) as a definitive entity, defined as a mature CD30-positive T-cell lymphoma, confined by a fibrous capsule, in a breast implant setting. Only few B-cell lymphomas have been reported in the literature to be associated with breast implants. Here we report two EBV-positive Diffuse Large B-cell lymphomas (EBV + DLBCL) in relation to a breast implant, both expressing CD30 as well as EBV latency type 3. Both lesions were considered as DLBCL associated with chronic inflammation (CI-DLBCL), but one presented as a 7 cm solid mass, while the other presented as a fibrin-associated DLBCL (FA-DLBCL) in an HIV patient. Clinically, both are in complete remission 6 months or longer after capsulectomy and graft removal, without additional chemotherapy.Such cases, characterized by large CD30-positive cells, can easily be misdiagnosed as BIA-ALCL if the cell of origin is not further established. Therefore, a diagnostic panel including lineage-specific B-and T-cell markers and EBER in situ hybridization is essential to recognize this rare entity, to understand lymphomagenesis, to predict outcome and to define clinical approach.


Asunto(s)
Implantes de Mama , Neoplasias de la Mama , Infecciones por VIH , Linfoma de Células B Grandes Difuso , Linfoma Anaplásico de Células Grandes , Humanos , Femenino , Implantes de Mama/efectos adversos , Herpesvirus Humano 4 , Antígeno Ki-1 , Neoplasias de la Mama/patología , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/etiología , Linfoma Anaplásico de Células Grandes/patología , Linfoma de Células B Grandes Difuso/diagnóstico
12.
Histopathology ; 61(1): 10-7, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22458667

RESUMEN

AIMS: To evaluate the reproducibility and reliability of the histomorphological criteria differentiating severe aplastic anaemia (SAA) and hypoplastic refractory cytopenia of childhood (RCC), the most frequently acquired hypocellular bone marrow conditions of childhood. METHODS AND RESULTS: We performed a double-blind interobserver study of 100 different cases of SAA and RCC among seven haematopathologists of the European Working Group of MDS in Childhood (EWOG-MDS) and the German SAA study. Cases with foci of typical myelodysplastic syndrome (MDS) morphology, such as patchy erythropoiesis with defective maturation, in an otherwise highly hypocellular or adipocytic bone marrow were classified as having RCC. Bone marrow samples without a patchy distribution, few scattered myeloid cells or haematopoietic aplasia were diagnosed as SAA. In only four of 100 cases did the reference pathologists not reach agreement regarding classification as SAA or RCC. The kappa index was 0.79. CONCLUSIONS: Our results show that the vast majority of SAA and RCC cases can be reliably differentiated by morphological means alone. A clear differentiation between SAA and RCC at presentation is mandatory for optimizing therapy strategies, and might be responsible for the fact that, in the German childhood SAA study, the probability of developing clonal disease after immunosuppressive therapy has dropped to 3%.


Asunto(s)
Anemia Aplásica/diagnóstico , Anemia Refractaria/diagnóstico , Células de la Médula Ósea/patología , Pancitopenia/diagnóstico , Anemia Refractaria/etiología , Niño , Preescolar , Diagnóstico Diferencial , Método Doble Ciego , Humanos , Pancitopenia/complicaciones , Estudios Prospectivos , Reproducibilidad de los Resultados
13.
Acta Cardiol ; 77(9): 791-804, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34565298

RESUMEN

BACKGROUND: Cardiac amyloidosis (CA) is often overlooked or misdiagnosed. Effects of growing disease awareness, diagnostic ameliorations and novel treatment options on CA diagnosis and management are scarcely reported. OBJECTIVE: To report trends in diagnosis, referral routes, clinical presentation, early onset diagnostic red flags and outcome in de novo CA subjects. METHODS: An unselected cohort of 139 de novo CA patients over an 8-year period in a tertiary referral hospital was recruited. RESULTS: Transthyretin (ATTR, 82%, n = 114) was the most common CA form; Light-chain (AL, 15%, n = 21) and secondary (AA, 3%, n = 4) are less prevalent. Increased awareness over time led to a marked ATTR diagnostic surge, steep non-invasive diagnostic approach increment and increased nuclear medicine and external cardiologist referrals (all p < 0.001). A total of 41% (n = 57/139) of patients were referred by non-cardiology specialist disciplines. Specific referral to rule out CA (24-36%) and diagnostic time lag from symptom onset (9 ± 12 to 8 ± 14 months), however, did not improve (all p > 0.050). Multiple early red flag events preceded CA diagnose several years in ATTR: Left ventricular hypertrophy (LVH, 60%, 4.9 ± 4.3 y), heart failure (54%, 2.5 ± 3.5 y), atrial fibrillation (47%, 5.9 ± 6.7 y), bilateral carpal tunnel syndrome (43%, 9.5 ± 5.7 y) and spinal stenosis (40%, 7.4 ± 6.5 y). LVH ≥ 12 mm was absent in 11% ATTR (n = 13/114) and 5% AL (n = 1/21) patients. Hypertension was common in both ATTR (n = 70/114, 62%) and AL (n = 10/21, 48%). 56% (n = 78/139) of CA presented with heart failure. Cumulative 1 and 5-year mortality of 10%/66%, 40%/52% and 75%/75% for ATTR, AL, and AA, respectively, remains high. CONCLUSIONS: Although CA diagnostic uptake and referral improve, specialist-specific disease and diagnostic red flag ignorance result in non-timely diagnosis and unfavourable outcome.


Asunto(s)
Neuropatías Amiloides Familiares , Fibrilación Atrial , Cardiomiopatías , Insuficiencia Cardíaca , Humanos , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/epidemiología , Neuropatías Amiloides Familiares/complicaciones , Fibrilación Atrial/complicaciones , Insuficiencia Cardíaca/complicaciones , Derivación y Consulta , Cardiomiopatías/diagnóstico , Cardiomiopatías/complicaciones
15.
Br J Haematol ; 147(5): 686-90, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19775296

RESUMEN

Classical Hodgkin lymphoma (cHL) is characterized by the presence of malignant Hodgkin and Reed Sternberg (HRS) cells. The scarcity of tumour cells in lymphoma biopsies has hampered genetic analyses of HRS cells, including microRNA (miRNA) expression profiling. We determined the expression of 360 miRNAs in microdissected HRS cells from nine cHL patients. These miRNA profiles were compared to those from four cHL cell lines and CD77+ B-cells, yielding a distinct cHL signature of 12 over- and three underexpressed miRNAs. Our data suggest that miRNAs are implicated in the pathogenesis of Hodgkin lymphoma and prompt further investigations concerning their role in cHL.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Enfermedad de Hodgkin/genética , MicroARNs/genética , ARN Neoplásico/genética , Células de Reed-Sternberg/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Centro Germinal/inmunología , Enfermedad de Hodgkin/patología , Humanos , Microdisección , Trihexosilceramidas/análisis , Células Tumorales Cultivadas
17.
Haematologica ; 92(7): 913-20, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17606441

RESUMEN

BACKGROUND AND OBJECTIVES: Classical Hodgkin's lymphoma (cHL) is a common malignant lymphoma characterized by the presence of large, usually multinucleated malignant Hodgkin and Reed Sternberg (HRS) cells which are thought to be derived from germinal center B-cells. In cHL, the HRS cells constitute less than 1% of the tumor volume; consequently the profile of genetic aberrations in cHL is still poorly understood. DESIGN AND METHODS: In this study, we subjected four commonly used cHL cell lines to array comparative genomic hybridization (aCGH) in order to delineate known chromosomal aberrations in more detail and to search for small hitherto undetected genomic imbalances. RESULTS: The aCGH profiles of the four cell lines tested confirmed the complex patterns of rearrangements previously demonstrated with M-FISH and chromosomal CGH (cCGH). Importantly, aCGH allowed a much more accurate delineation of imbalances as compared to previous studies performed at chromosomal level of resolution. Furthermore, we detected 35 hitherto undetected aberrations including a homozygous deletion of chromosomal region 15q26.2 in the cell line HDLM2 encompasing RGMA and CHD2 and an amplification of the STAT6 gene in cell line L1236 leading to STAT6 overexpression. Finally, in cell line KM-H2 we found a 2.35 Mb deletion at 16q12.1 putatively defining a small critical region for the recurrent 16q deletion in cHL. This region contains the CYLD gene, a known suppressor gene of the NF-mB pathway. INTERPRETATION AND CONCLUSIONS: aCGH was performed on four cHL cell lines leading to the improved delineation of known chromosomal imbalances and the detection of 35 hitherto undetected aberrations. More specifically, our results highlight STAT6 as a potential transcriptional target and identified RGMA, CHD2 and CYLD as candidate tumor suppressors in cHL.


Asunto(s)
Dosificación de Gen , Enfermedad de Hodgkin/genética , Línea Celular Tumoral , Aberraciones Cromosómicas , Análisis Citogenético , Proteínas de Unión al ADN/genética , Enzima Desubiquitinante CYLD , Regulación Neoplásica de la Expresión Génica , Enfermedad de Hodgkin/patología , Humanos , Proteínas de Neoplasias/genética , Factor de Transcripción STAT6/genética , Proteínas Supresoras de Tumor/genética
19.
J Clin Oncol ; 23(28): 7060-8, 2005 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-16129841

RESUMEN

PURPOSE: The reliability of immunohistochemistry for subdividing diffuse large B-cell lymphomas (DLBCL) into germinal center B-cell-like (GCB) and non-GCB prognostic subgroups is debated. In this study we evaluated the prognostic significance of such subgrouping on a series of 153 DLBCL patients. Furthermore, we investigated whether both subgroups could comprise clinicopathologic entities recognized by their morphology and characterized by a distinct phenotype, specific genetic abnormalities, and clinical characteristics. PATIENTS AND METHODS: All samples from patients were reviewed and morphologically subdivided into large cleaved, immunoblastic, and not otherwise specified DLBCL. GCB and non-GCB immunohistochemical profiles were established. The presence of chromosomal translocations involving BCL2, BCL6, and MYC and/or rearrangements of these genes was investigated. RESULTS: Subdividing DLBCL with either a GCB or non-GCB immunophenotypic profile was not of prognostic significance. Nevertheless, CD10 expression was a predictor of favorable outcome, whereas high bcl-2 expression and BCL6 rearrangement were adverse predictors of disease-free survival. Interestingly, large cleaved DLBCL was clearly associated with a GCB immunophenotypic profile, CD10 expression, BCL2 rearrangement, age younger than 60 years, and low to low/intermediate International Prognostic Index risk, but was not of prognostic significance. In contrast, immunoblastic morphology was associated with a non-GCB profile and was a significant predictor of unfavorable DFS. CONCLUSION: Subdividing DLBCL into subgroups based on their immunohistochemical profile was not of prognostic significance. Nevertheless, it allowed the additional characterization of two lymphoma subgroups previously recognized in the Working Formulation. Both correspond to two distinct clinicopathologic entities within the DLBCL.


Asunto(s)
Linfoma de Células B Grandes Difuso/patología , Linfoma Inmunoblástico de Células Grandes/patología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Proteínas de Unión al ADN/genética , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Linfoma Inmunoblástico de Células Grandes/diagnóstico , Linfoma Inmunoblástico de Células Grandes/genética , Masculino , Persona de Mediana Edad , Neprilisina/biosíntesis , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-6 , Reproducibilidad de los Resultados , Estudios Retrospectivos , Análisis de Supervivencia
20.
PLoS One ; 9(7): e102977, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25057852

RESUMEN

Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma cytogenetically characterized by isochromosome 7q [i(7)(q10)], of which the molecular consequences remain unknown. We report here results of an integrative genomic and transcriptomic (expression microarray and RNA-sequencing) study of six i(7)(q10)-positive HSTL cases, including HSTL-derived cell line (DERL-2), and three cases with ring 7 [r(7)], the recently identified rare variant aberration. Using high resolution array CGH, we profiled all cases and mapped the common deleted region (CDR) at 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp) and the common gained region (CGR) at 7q22.11q31.1 (38.77 Mb; 86259620-124892276 bp). Interestingly, CDR spans a smaller region of 13 Mb (86259620-99271246 bp) constantly amplified in cases with r(7). In addition, we found that TCRG (7p14.1) and TCRB (7q32) are involved in formation of r(7), which seems to be a byproduct of illegitimate somatic rearrangement of both loci. Further transcriptomic analysis has not identified any CDR-related candidate tumor suppressor gene. Instead, loss of 7p22.1p14.1 correlated with an enhanced expression of CHN2 (7p14.1) and the encoded ß2-chimerin. Gain and amplification of 7q22.11q31.1 are associated with an increased expression of several genes postulated to be implicated in cancer, including RUNDC3B, PPP1R9A and ABCB1, a known multidrug resistance gene. RNA-sequencing did not identify any disease-defining mutation or gene fusion. Thus, chromosome 7 imbalances remain the only driver events detected in this tumor. We hypothesize that the Δ7p22.1p14.1-associated enhanced expression of CHN2/ß2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic δγT-cells and underlies their intrinsic chemoresistance. Finally, our study confirms the previously described gene expression profile of HSTL and identifies a set of 24 genes, including three located on chromosome 7 (CHN2, ABCB1 and PPP1R9A), distinguishing HSTL from other malignancies.


Asunto(s)
Proteínas Quimerinas/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 7 , Neoplasias Hepáticas/genética , Linfoma de Células T/genética , Proteínas de Microfilamentos/genética , Proteínas de Neoplasias/genética , Proteínas del Tejido Nervioso/genética , Neoplasias del Bazo/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adolescente , Adulto , Niño , Proteínas Quimerinas/metabolismo , Mapeo Cromosómico , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Sitios Genéticos , Genoma Humano , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Linfoma de Células T/metabolismo , Linfoma de Células T/patología , Masculino , Proteínas de Microfilamentos/metabolismo , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neoplasias del Bazo/metabolismo , Neoplasias del Bazo/patología , Transcriptoma
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