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1.
Pathologica ; 116(3): 163-169, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38979590

RESUMEN

The 5th WHO classification of thoracic tumours includes thoracic SMARCA4-deficient undifferentiated tumour (SMARCA4-UT) among the "other epithelial tumours of the lung" chapter. Herein, we present a case of undifferentiated thoracic neoplasm with retention of SMARCA4 expression, lack of NUT fusion protein and loss of SMARCB1/INI1 expression. After presenting the clinical and pathological features of the tumour, we carried out a review of the literature on the same topic. Albeit very rare, we believe this entity should be included in the heterogeneous group of undifferentiated neoplasms of the thorax.


Asunto(s)
ADN Helicasas , Proteína SMARCB1 , Neoplasias Torácicas , Factores de Transcripción , Humanos , Proteína SMARCB1/deficiencia , Proteína SMARCB1/genética , Factores de Transcripción/genética , Factores de Transcripción/deficiencia , Neoplasias Torácicas/patología , Neoplasias Torácicas/genética , ADN Helicasas/deficiencia , ADN Helicasas/genética , Proteínas Nucleares/genética , Proteínas Nucleares/deficiencia , Masculino , Femenino , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico
2.
Pathologica ; 116(1): 13-21, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38482671

RESUMEN

The WHO Classification of Tumors, Thoracic Tumors, 5th edition, has outlined the use of TTF-1 and ΔNP63/P40 to discriminate between adenocarcinoma and squamous cell carcinoma. In 2015, the first description of a rare non-small cell lung carcinoma featuring co-expression of glandular and squamous differentiation within most of the same individual tumor cells was reported on, with ultrastructural and molecular demonstration of such a biphenotypic differentiation. We herein describe an additional case of this rare tumor entity, which is confirmed to be an aggressive neoplasm despite potential targets of therapy.


Asunto(s)
Adenocarcinoma , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/patología , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Pulmón/patología , Pronóstico , Biomarcadores de Tumor
3.
Blood ; 137(10): 1365-1376, 2021 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-32992344

RESUMEN

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed "satellites," were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.


Asunto(s)
Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Frecuencia de los Genes , Reordenamiento Génico , Humanos , Hipermutación Somática de Inmunoglobulina
4.
Acta Haematol ; 146(1): 58-64, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36198282

RESUMEN

More than 95% of patients with acute promyelocytic leukemia (APL) are characterized by the reciprocal translocation t(15;17)(q24;21), which involves the promyelocytic leukemia protein (PML) gene on chromosome 15 and the retinoic acid receptor-α (RARA) gene on chromosome 17, leading to the production of the PML::RARA chimeric gene. Additional chromosomal abnormalities are described in all acute myeloid leukemias and occur in approximately one-third of patients with newly diagnosed APL. Here, we report the case of de novo APL showing the classical t(15;17)(q24;q21), a deletion of the short arm of chromosome 6 (6p), and a noncanonical molecular variant of the PML::RARA transcript. Nevertheless, the patient achieved complete remission after treatment with conventional therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Notwithstanding that the molecular pathogenesis of this type of atypical variant still remains unknown, we conclude that this atypical PML::RARA bcr2 fusion gene associated with del(6p) does not seem to alter the effectiveness of combined treatment with ATRA and ATO.


Asunto(s)
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Tretinoina/uso terapéutico , Proteína de la Leucemia Promielocítica/genética , Proteínas de Fusión Oncogénica/genética
5.
Pathologica ; 113(4): 262-271, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34463674

RESUMEN

Next Generation Sequencing (NGS) is increasingly used in diagnostic centers for the assessment of genomic alterations to select patients for precision oncology. The Italian Society of Anatomic Pathology and Diagnostic Cytopathology (SIAPEC) through the Molecular Pathology and Predictive Medicine Study Group (PMMP) has been following the progressive development of centers that have adopted NGS technology in diagnostics over time. In July 2017, a study network on massive parallel sequencing was activated in Italy and recognized as the NGS SIAPeC National Network by the SIAPeC Scientific Society Board. Since then, activities have been implemented within the network that provide for alignment of laboratories through diagnostic concordance analysis and monitoring of centers adhering to the Network. Recently, considering the growing need for extended genomic analyses, the PMMP distributed a national survey to assess activities related to the use of genomic diagnostics in oncology within the NGS SIAPEC National Network.Thirty centers participated in the survey. Eighty percent of the centers are laboratories within Pathology Departments. The distribution of laboratories in the country, the diagnostic laboratory/population ratio, the staff dedicated, the type and number of sequencing and mechatronics platforms available, the genomic panels utilized, and the type and number of diagnostic tests carried out in the last year in each center, are reported.The centers were also asked whether they participated in a multidisciplinary Molecular Tumor Board (MTB) for management of patients. Thirty percent of the centers had a MTB that was ratified by regional decree. The professionals most frequently involved in the core team of the MTB are the pathologist, oncologist, molecular biologist, geneticist, pharmacologist, and bioinformatician.The data from this survey indicate that NGS diagnostics in Italy is still heterogeneous in terms of geographical distribution and the characteristics of laboratories and diagnostic test performed. The implementation of activities that favors harmonization, the logistics and the convergence of biological material in reference centers for molecular analyses is a priority for the development of a functional laboratory network.


Asunto(s)
Neoplasias , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Italia , Neoplasias/diagnóstico , Neoplasias/epidemiología , Neoplasias/genética , Patología Molecular , Medicina de Precisión
6.
Transpl Infect Dis ; 20(3): e12880, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29514393

RESUMEN

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) outbreaks are described in solid organ transplant recipients. Few reports suggest interhuman transmission with important infection control implications. We described a large PJP outbreak in heart transplant (HTx) recipients. METHODS: Six cases of PJP occurred in HTx recipients within 10 months in our hospital. Demographics, clinical characteristics, treatment and outcomes were described. To identify contacts among individuals a review of all dates of out-patient visits and patient hospitalizations was performed. Cross exposure was also investigated using genotyping on PJ isolates. RESULTS: At the time of PJP-related hospitalization, patients' mean age was 49 ± standard deviation 4 years, median time from HTx was 8 (25%-75% interquartile range [Q1-Q3] 5-12) months and none of the cases were on prophylaxis. At PJP-related admission, 5 patients had CMV reactivation, of whom 4 were on antiviral preemptive treatment. Median in-hospital stay was 30 (Q1-Q3, 28-48) days; and 2 cases required intensive care unit admission. All patients survived beyond 2 years. Transmission map analysis suggested interhuman transmission in all cases (presumed incubation period, median 90 [Q1-Q3, 64-91] days). Genotyping was performed in 4 cases, demonstrating the same PJ strain in 3 cases. CONCLUSIONS: We described a large PJP cluster among HTx recipients, supporting the nosocomial acquisition of PJP through interhuman transmission. Based on this experience, extended prophylaxis for more than 6 months after HTx could be considered in specific settings. Further work is required to understand its optimal duration and timing based on individual risk factor profiles and to define standardized countermeasures to prevent and limit PJP outbreaks.


Asunto(s)
Brotes de Enfermedades , Trasplante de Corazón/efectos adversos , Pneumocystis carinii/aislamiento & purificación , Neumonía por Pneumocystis/epidemiología , Receptores de Trasplantes/estadística & datos numéricos , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Control de Infecciones , Masculino , Persona de Mediana Edad , Neumonía por Pneumocystis/transmisión , Factores de Riesgo
7.
Nature ; 486(7404): 532-6, 2012 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-22722830

RESUMEN

A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Mutación/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Alelos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Línea Celular Tumoral , Cetuximab , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Genes ras/genética , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Panitumumab , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas p21(ras)
9.
Blood ; 125(5): 856-9, 2015 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-25634617

RESUMEN

An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.


Asunto(s)
Regulación Leucémica de la Expresión Génica , Reordenamiento Génico de Cadena Pesada de Linfocito B/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Anciano , Antineoplásicos/uso terapéutico , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/patología , Femenino , Heterogeneidad Genética , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Hipermutación Somática de Inmunoglobulina , Análisis de Supervivencia , Tiempo de Tratamiento , Resultado del Tratamiento
10.
Lancet Oncol ; 17(6): 738-746, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27108243

RESUMEN

BACKGROUND: We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2-amplified metastatic colorectal cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer. METHODS: HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33. FINDINGS: Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51-127), eight (30%, 95% CI 14-50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI -3 to 11) achieving a complete response, and seven (26%, 95% CI 9-43) achieving partial responses; 12 (44%, 95% CI 25-63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events. INTERPRETATION: The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer. FUNDING: Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Terapia Molecular Dirigida , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor ErbB-2/antagonistas & inhibidores , Adulto , Anciano , Biomarcadores de Tumor , Codón/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Lapatinib , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Quinazolinas/administración & dosificación , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Terapia Recuperativa , Tasa de Supervivencia , Trastuzumab/administración & dosificación
11.
Br J Cancer ; 113(12): 1730-4, 2015 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-26633560

RESUMEN

BACKGROUND: Activated anaplastic lymphoma kinase (ALK) gene fusions are recurrent events in a small fraction of colorectal cancers (CRCs), although these events have not yet been exploited as in other malignancies. METHODS: We detected ALK protein expression by immunohistochemistry and gene rearrangements by fluorescence in situ hybridisation in the ALKA-372-001 phase I study of the pan-Trk, ROS1, and ALK inhibitor entrectinib. One out of 487 CRCs showed ALK positivity with a peculiar pattern that prompted further characterisation by targeted sequencing using anchored multiplex PCR. RESULTS: A novel ALK fusion with the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene (CAD-ALK fusion gene) was identified. It resulted from inversion within chromosome 2 and the fusion of exons 1-35 of CAD with exons 20-29 of ALK. After failure of previous standard therapies, treatment of this patient with the ALK inhibitor entrectinib resulted in a durable objective tumour response. CONCLUSIONS: We describe the novel CAD-ALK rearrangement as an oncogene and provide the first evidence of its drugability as a new molecular target in CRC.


Asunto(s)
Antineoplásicos/uso terapéutico , Aspartato Carbamoiltransferasa/genética , Benzamidas/uso terapéutico , Carbamoil-Fosfato Sintasa (Glutamina-Hidrolizante)/genética , Neoplasias Colorrectales/tratamiento farmacológico , Dihidroorotasa/genética , Reordenamiento Génico , Indazoles/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/genética , Quinasa de Linfoma Anaplásico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Humanos , Persona de Mediana Edad
12.
Mod Pathol ; 28(11): 1481-91, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26449765

RESUMEN

We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrollment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N=256) and clinical validation (N=830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.


Asunto(s)
Neoplasias Colorrectales/genética , Perfilación de la Expresión Génica/métodos , Hibridación Fluorescente in Situ/métodos , Selección de Paciente , Receptor ErbB-2/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Área Bajo la Curva , Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/clasificación , Neoplasias Colorrectales/tratamiento farmacológico , Femenino , Perfilación de la Expresión Génica/normas , Humanos , Inmunohistoquímica/métodos , Lapatinib , Masculino , Persona de Mediana Edad , Quinazolinas , Curva ROC , Trastuzumab
13.
Blood ; 121(22): 4521-8, 2013 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-23596047

RESUMEN

Chronic lymphocytic leukemia (CLL) -like monoclonal B-cell lymphocytosis (MBL) shares common immunophenotype and cytogenetic abnormalities with CLL, from which it is discriminated by a cutoff value of 5 × 10(9)/L circulating clonal B cells. However, the clonal size in MBL is extremely variable and allows discrimination of two distinct entities (high-count [HC] and low-count [LC]-MBL) based on a cutoff value of 0.5 × 10(9)/L clonal B cells. HC-MBL is associated with lymphocytosis and progresses to CLL requiring treatment at a rate of 1.1% per year, whereas LC-MBL is found in the general population only through high-sensitivity techniques and carries limited, if any, risk of progression. We performed an immunogenetic profiling of 333 cases with CLL-like MBL supplemented by detailed comparisons with CLL, focusing especially on CLL Rai stage 0 (CLL-0). LC- and HC-MBL had similar somatic hypermutation status, yet different IGHV gene repertoires and frequencies of B-cell receptor (BcR) stereotypy. In particular, stereotyped BcRs were infrequent in LC-MBL and were often not CLL specific. In contrast, HC-MBL exhibited clear immunogenetic similarities to CLL-0. These findings indicate that LC-MBL may not represent a true preleukemic condition, thus differing from HC-MBL/CLL-0 in which the identification of factors endowing malignant potential is strongly warranted.


Asunto(s)
Linfocitos B/inmunología , Inmunogenética/métodos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Linfocitosis/inmunología , Lesiones Precancerosas/inmunología , Linfocitos B/patología , Células Clonales/inmunología , Células Clonales/patología , Reordenamiento Génico de Linfocito B/inmunología , Humanos , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B/patología , Recuento de Linfocitos , Linfocitosis/patología , Lesiones Precancerosas/patología , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología
14.
Lancet Oncol ; 14(10): 981-8, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23883922

RESUMEN

BACKGROUND: Erlotinib is registered for treatment of all patients with advanced non-small-cell lung cancer (NSCLC). However, its efficacy for treatment of patients whose tumours are EGFR wild-type-which includes most patients-is still contentious. We assessed the efficacy of erlotinib compared with a standard second-line chemotherapy in such patients. METHODS: We did this randomised controlled trial in 52 Italian hospitals. We enrolled patients who had metastatic NSCLC, had had platinum-based chemotherapy, and had wild-type EGFR as assessed by direct sequencing. Patients were randomly assigned centrally (1:1) to receive either erlotinib orally 150 mg/day or docetaxel intravenously 75 mg/m(2) every 21 days or 35 mg/m(2) on days 1, 8, and 15, every 28 days. Randomisation was stratified by centre, stage, type of first-line chemotherapy, and performance status. Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation, investigators who analysed results were. The primary endpoint was overall survival in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT00637910. FINDINGS: We screened 702 patients, of whom we genotyped 540. 222 patients were enrolled (110 assigned to docetaxel vs 112 assigned to erlotinib). Median overall survival was 8·2 months (95% CI 5·8-10·9) with docetaxel versus 5·4 months (4·5-6·8) with erlotinib (adjusted hazard ratio [HR] 0·73, 95% CI 0·53-1·00; p=0·05). Progression-free survival was significantly better with docetaxel than with erlotinib: median progression-free survival was 2·9 months (95% CI 2·4-3·8) with docetaxel versus 2·4 months (2·1-2·6) with erlotinib (adjusted HR 0·71, 95% CI 0·53-0·95; p=0·02). The most common grade 3-4 toxic effects were: low absolute neutrophil count (21 [20%] of 104 in the docetaxel group vs none of 107 in the erlotinib group), skin toxic effects (none vs 15 [14%]), and asthenia (ten [10%] vs six [6%]). INTERPRETATION: Our results show that chemotherapy is more effective than erlotinib for second-line treatment for previously treated patients with NSCLC who have wild-type EGFR tumours.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Taxoides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Docetaxel , Receptores ErbB/genética , Clorhidrato de Erlotinib , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Proteínas ras/genética
15.
Int J Cancer ; 133(5): 1259-65, 2013 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-23404247

RESUMEN

KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) targeted therapies. Using preclinical models and patients' samples we recently reported that the emergence of KRAS mutations but also KRAS amplification is associated with acquired resistance to the EGFR inhibitors cetuximab or panitumumab. We reasoned that KRAS amplification may also be responsible for primary resistance to these agents. Furthermore, while the prevalence of KRAS mutations has been well established in CRC, little is known about the frequency of KRAS amplification in large CRC series. We performed a screening of 1,039 CRC samples to assess the prevalence of KRAS amplification in this tumor type and further evaluated the role of this genetic alteration on the sensitivity to anti EGFR therapies. We detected KRAS amplification in 7/1,039 (0.67%) and 1/102 evaluable CRC specimens and cell lines, respectively. KRAS amplification was mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to anti-EGFR inhibitors. Although KRAS amplification is an infrequent event in CRC, it might be responsible for precluding response to anti-EGFR treatment in a small proportion of patients.


Asunto(s)
Neoplasias Colorrectales/genética , Receptores ErbB/antagonistas & inhibidores , Amplificación de Genes , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Proteínas Proto-Oncogénicas p21(ras) , Estudios Retrospectivos
17.
JTO Clin Res Rep ; 4(11): 100555, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38047274

RESUMEN

ROS1 tyrosine kinase inhibitors (TKIs) were found to provide a substantial clinical benefit for patients with advanced ROS1-positive (ROS1+) NSCLC. Nevertheless, TKI resistance inevitably develops with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to entrectinib. Hereby, we report the case of a patient with ROS1+ NSCLC in which F2004V-acquired mutation was detected on a site of disease progression, after entrectinib and crizotinib failure. A subsequent treatment with next-generation TKI repotrectinib led to disease response, providing the first clinical evidence of activity of repotrectinib against F2004V resistance mutation.

18.
Mol Genet Metab ; 105(4): 687-9, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22341397

RESUMEN

The Anderson-Fabry disease (AFD) is an X-linked glycosphingolipidosis leading to a progressive systemic disease. A particular variant of the disease of AFD presents only with left ventricular hypertrophy (LVH). Molecular diagnosis with bidirectional sequencing fails to detect genomic re-arrangements in female patients because of the presence of the wt allele. We here propose a quantitative PCR-based method alternative/complementary to the MLPA.


Asunto(s)
Enfermedad de Fabry/genética , Duplicación de Gen , Hipertrofia Ventricular Izquierda/genética , Reacción en Cadena de la Polimerasa/métodos , Eliminación de Secuencia , alfa-Galactosidasa/genética , Estudios de Cohortes , ADN/análisis , ADN/genética , Estudios de Factibilidad , Femenino , Humanos , Persona de Mediana Edad
20.
Hematol Rep ; 13(1): 8795, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33824712

RESUMEN

The cytogenetic hallmark of Chronic Myeloid Leukemia (CML) is the presence of Philadelphia (Ph) chromosome, which results from a reciprocal translocation t(9;22)(q34;q11). In this report, we describe a CML patient with no evidence of Ph chromosome but trisomy of chromosome 8 as single cytogenetic abnormality and a typical e14a2 (b3a2) BCR-ABL1 fusion transcript. Fluorescence In Situ Hybridization (FISH) analysis revealed an uncommon signal pattern: the fusion signals were located on both copies of chromosome 22. During the course of the disease the appearance of the p.(Tyr315Ile) mutation was recorded. To the best of our knowledge this is the first Ph chromosome-negative CML case with e14a2 (b3a2) BCR-ABL1 transcript and p.(Tyr315Ile) mutation.

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