RESUMEN
The singular BRCA1/2 mutational landscape of Asturias is updated 10 years after the first study. We analyzed BRCA1 and BRCA2 pathogenic variants in 1653 index cases. In total, 238 families were identified to carry a pathogenic variant, 163 families in BRCA1 and 75 families in BRCA2. This yielded a prevalence rate of 14.4%. Seven recurrent variants were found accounting for 55% of the cases. Among them, three are widely distributed (BRCA1 c.211A>G, c.470_471del and c.3331_3334del) and four had been reported as novel in Asturias: two in BRCA1 (c.1674del and c.2901_2902dup) and two in BRCA2 (c.2095C>T and c.4040_4035delinsC). A common haplotype was established for all recurrent variants indicating a shared ancestral origin. Three splicing analyses are shown: BRCA1:c.5152+3A>C and BRCA1:c.5333-3T>G that lead to skipping of exon 18, and 22 respectively, and BRCA1:c.5278-1G>T giving rise to two transcripts, one lacking exon 21 (p.Ille1760Glyfs*60) and one lacking the first 8 nucleotides of exon 21 (p.Phe1761Asnfs*14), supporting pathogenicity for these variants.
RESUMEN
BACKGROUND: We performed a comparative analysis between an organ-preservation protocol and surgery followed by radiotherapy in patients with locally advanced squamous cell carcinoma of the larynx and hypopharynx; Methods: 60 previously untreated patients who were treated with induction chemotherapy followed by chemoradiotherapy in responders were compared with a control group of 60 patients treated with up-front surgery. Both groups were statistically comparable, according to the subsite, TNM (tumor-node-metastasis) stage, age, and sex; Results: Mean age was 58 years and 92% were male. No significant statistical difference was observed for overall survival (OS) (HR 0.75; 95% CI 0.48-1.18; P = 0.22) and disease-specific survival (DSS) (HR 0.98; 95% CI 0.52-1.83, P = 0.96). Also, there was no significant difference for recurrence-free survival (HR 0.931; 95% CI 0.57-1.71; P = 0.81), metastases-free survival (HR 2.23; 95% CI 0.67-7.41; P = 0.19), and the appearance of second primary tumors (HR 1.22; 95% CI 0.51-2.88; P = 0.64); Conclusions: The results of the organ-preservation approach did not appear inferior to those of surgery plus (chemo)radiotherapy for patients with T3/T4a larynx and T2-T4a hypopharynx cancer with respect to OS and DSS, locoregional control and metastases-free survival.
RESUMEN
BACKGROUND & AIMS: Although there is a genetic predisposition to colorectal cancer (CRC), few of the genes that affect risk have been identified. We performed whole-exome sequence analysis of individuals in a high-risk family without mutations in genes previously associated with CRC risk to identify variants associated with inherited CRC. METHODS: We collected blood samples from 3 relatives with CRC in Spain (65, 62, and 40 years old at diagnosis) and performed whole-exome sequence analyses. Rare missense, truncating or splice-site variants shared by the 3 relatives were selected. We used targeted pooled DNA amplification followed by next generation sequencing to screen for mutations in candidate genes in 547 additional hereditary and/or early-onset CRC cases (502 additional families). We carried out protein-dependent yeast growth assays and transfection studies in the HT29 human CRC cell line to test the effects of the identified variants. RESULTS: A total of 42 unique or rare (population minor allele frequency below 1%) nonsynonymous genetic variants in 38 genes were shared by all 3 relatives. We selected the BRF1 gene, which encodes an RNA polymerase III transcription initiation factor subunit for further analysis, based on the predicted effect of the identified variant and previous association of BRF1 with cancer. Previously unreported or rare germline variants in BRF1 were identified in 11 of 503 CRC families, a significantly greater proportion than in the control population (34 of 4300). Seven of the identified variants (1 detected in 2 families) affected BRF1 mRNA splicing, protein stability, or expression and/or function. CONCLUSIONS: In an analysis of families with a history of CRC, we associated germline mutations in BRF1 with predisposition to CRC. We associated deleterious BRF1 variants with 1.4% of familial CRC cases, in individuals without mutations in high-penetrance genes previously associated with CRC. Our findings add additional evidence to the link between defects in genes that regulate ribosome synthesis and risk of CRC.
Asunto(s)
Neoplasias Colorrectales/genética , Mutación de Línea Germinal/genética , Factores Asociados con la Proteína de Unión a TATA/genética , Adulto , Anciano , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Linaje , EspañaRESUMEN
BACKGROUND: DICER1 syndrome is a pediatric cancer predisposition condition causing a variety of tumor types in children and young adults. In this report we studied a family with two relatives presenting a variety of neoplastic conditions at childhood. METHODS: Germ-line mutation screening of the complete coding region of the DICER1 gene in genomic DNA from the proband was performed. The presence of somatic DICER1 mutation and further alterations in driver genes was investigated in genomic DNA obtained from available tumor samples. RESULTS: A nonsense germ-line mutation in DICER1 causing a truncated protein at the IIIb domain level was identified segregating within a family including two affected relatives who developed in one case cystic nephroma and pleuropulmonary blastoma, and rhabdomyosarcoma and multinodular goiter in the other. Additional in trans DICER1 missense somatic mutations in the IIIb DICER1 domain were found both in the cystic nephroma and in the rhabdomyosarcoma, suggesting that neoplasms in this family might arise from the unusual two-hit mechanism for DICER-derived tumorigenesis in which after the presence of a truncated constitutive protein, a neomorphic DICER1 activity is somatically adquired. Additional genetic alterations, such as TP53 mutations, were identified in the rhabdomyosarcoma. CONCLUSIONS: Besides DICER1 loss of standard activity, oncogenic cooperation of other genes, as mutated TP53, may involve developing higher grade tumors within this syndrome. Given the broad clinical spectrum that may arise, genetic counseling and close surveillance must be offered to all family members at risk of DICER1 syndrome.
Asunto(s)
ARN Helicasas DEAD-box/genética , Mutación de Línea Germinal , Nefroma Mesoblástico/genética , Blastoma Pulmonar/genética , Rabdomiosarcoma/genética , Ribonucleasa III/genética , Preescolar , Codón sin Sentido , ARN Helicasas DEAD-box/química , ARN Helicasas DEAD-box/metabolismo , Femenino , Humanos , Masculino , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patología , Nefroma Mesoblástico/patología , Linaje , Dominios Proteicos , Blastoma Pulmonar/patología , Rabdomiosarcoma/patología , Ribonucleasa III/química , Ribonucleasa III/metabolismo , Proteína p53 Supresora de Tumor/genética , Adulto JovenRESUMEN
OBJECTIVE: Endometrial cancer is the second most frequent neoplasm in women with Lynch syndrome (LS). We sought to assess whether analyzing women with endometrial cancer would identify families with LS not identified with current clinical criteria. METHODS: We included women diagnosed with endometrial cancer younger than 50 years and also older if they had a family cancer history associated with LS. In blood samples obtained, we analyzed mutations in mismatch repair (MMR) genes, as well as protein expression by immunohistochemistry and microsatellite instability (MSI) in tumour tissue. RESULTS: A total of 103 patients were enrolled. We detected 14 pathogenic mutations and 4 genetic variants of unknown clinical significance in MMR genes. We found MSI in 41.66% of the women with a pathogenic mutation. In this group, 76.92% showed loss of at least one MMR protein. Women with mutations were younger at diagnosis, but all of them had a family history compatible with LS. CONCLUSIONS: Analysis of the MMR genes, in particular MSH6, seems to be appropriate in women with endometrial cancer and a family history of tumours associated with LS.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Neoplasias Endometriales/genética , Inestabilidad de Microsatélites , Adulto , Factores de Edad , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/genética , Neoplasias Endometriales/química , Femenino , Humanos , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL/análisis , Homólogo 1 de la Proteína MutL/genética , Proteína 2 Homóloga a MutS/análisis , Proteína 2 Homóloga a MutS/genética , Mutación , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Identification of genes associated with hereditary cancers facilitates management of patients with family histories of cancer. We performed exome sequencing of DNA from 3 individuals from a family with colorectal cancer who met the Amsterdam criteria for risk of hereditary nonpolyposis colorectal cancer. These individuals had mismatch repair-proficient tumors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene (FAN1), which encodes a nuclease involved in DNA inter-strand cross-link repair. We sequenced FAN1 in 176 additional families with histories of colorectal cancer and performed in vitro functional analyses of the mutant forms of FAN1 identified. We detected FAN1 mutations in approximately 3% of families who met the Amsterdam criteria and had mismatch repair-proficient cancers with no previously associated mutations. These findings link colorectal cancer predisposition to the Fanconi anemia DNA repair pathway, supporting the connection between genome integrity and cancer risk.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación del ADN/genética , Exodesoxirribonucleasas/genética , Mutación de Línea Germinal , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Preescolar , Neoplasias Colorrectales Hereditarias sin Poliposis/enzimología , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Endodesoxirribonucleasas , Exodesoxirribonucleasas/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Células HEK293 , Herencia , Humanos , Masculino , Persona de Mediana Edad , Enzimas Multifuncionales , Linaje , Fenotipo , Adulto JovenAsunto(s)
Antineoplásicos/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Erupciones por Medicamentos/etiología , Foliculitis/inducido químicamente , Neoplasias Renales/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/efectos adversos , Carcinoma de Células Renales/secundario , Erupciones por Medicamentos/patología , Foliculitis/patología , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Niacinamida/efectos adversos , Sorafenib , Factores de TiempoRESUMEN
BACKGROUND: The prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families. The contribution of these mutations to hereditary breast and ovarian cancer has not been previously investigated in Asturian populations (Northern Spain). METHODS: In the present work, 256 unrelated high-risk probands with breast and/or ovarian cancer from families living in Asturias were analyzed for the presence of a BRCA1 or BRCA2 gene mutation from October 2007 to May 2012. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened both by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: A total of 59 families (23%) were found to carry a pathogenic germ line mutation, 39 in BRCA1 and 20 in BRCA2. Twenty nine additional families (12%) carried an unknown significance variant. We detected 28 distinct pathogenic mutations (16 in BRCA1 and 12 in BRCA2), of which 3 mutations in BRCA1 (c.1674delA, c.1965C>A and c.2900_2901dupCT) and 5 in BRCA2 (c.262_263delCT, c.2095C>T, c.3263dupC, c.4030_4035delinsC, c.8042_8043delCA) had not been previously described.The novel mutations c.2900_2901dupCT in BRCA1 and c.4030_4035delinsC in BRCA2 occurred in 8 and 6 families respectively and clustered in two separated small geographically isolated areas suggesting a founder effect. These 2 mutations, together with the Galician BRCA1 mutation c.211A>G (9 families), and the common BRCA1 mutation c.3331_3334delCAAG (6 families), account for approximately 50% of all affected families. By contrast, very frequent mutations in other Spanish series such as the BRCA1 Ashkenazi founder mutation c.68_69delAG, was found in only one family. CONCLUSIONS: In this study we report the BRCA1 and BRCA2 spectrum of mutations and their geographical distribution in Asturias, which largely differ from other areas of Spain. Our findings may help design a first step recurrent mutation panel for screening high-risk breast and/or ovarian cancer families from this specific area.
Asunto(s)
Neoplasias de la Mama/genética , Análisis Mutacional de ADN , Genes BRCA1 , Genes BRCA2 , Neoplasias Ováricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , EspañaRESUMEN
Introducción y objetivos: Los carcinomas de orofaringe son neoplasias agresivas habitualmente diagnosticadas en estadios avanzados, siendo su tratamiento óptimo controvertido. El objetivo de este estudio es comparar los resultados oncológicos y funcionales de pacientes tratados con radioterapia (±quimioterapia concomitante) con otros tratados mediante cirugía (±radioterapia complementaria). Métodos: Se realizó un estudio retrospectivo en 50 pacientes con carcinoma epidermoide de orofaringe tratados con radioterapia (más quimioterapia concomitante en casos avanzados) entre 1998 y 2008, comparándolos con pacientes con el mismo estadio y localización tratados con cirugía (más radioterapia complementaria en casos avanzados). Ambos grupos se clasificaron de la siguiente manera: 10% estadio I, 12% en estadio II, 16% en estadio III, 48% en estadio IVa y 14% en estadio IVb. Resultados: La supervivencia específica para la enfermedad a los 5 años fue del 33% para el grupo de radioterapia y del 52% para el grupo de cirugía (p = 0,17). En tumores en estadios I y II, esta supervivencia específica fue del 82% en los tratados con radioterapia y del 70% en los tratados con cirugía. En estadios III y IV la supervivencia era mayor en los pacientes tratados con cirugía (47 vs 17%). Los resultados funcionales fueron similares en ambos grupos, presentando mayor preservación anatómica y funcional de la laringe el grupo de radioterapia, mientras que el grupo quirúrgico obtuvo mejores resultados para la alimentación oral. Conclusiones: El pronóstico de los pacientes con carcinomas epidermoide de orofaringe es pobre. Los resultados oncológicos del tratamiento con radioterapia y cirugía son similares para los estadios I y II. En estadios III y IV la supervivencia es mayor en los pacientes tratados mediante cirugía. Los resultados funcionales son también similares en ambos grupos (AU)
Introduction and objectives: Squamous cell carcinomas of the oropharynx are aggressive tumours usually diagnosed at advanced stage. Their optimal treatment has not been established. The aim of this study was to compare the oncological and functional outcomes in patients with carcinomas of the oropharynx treated by radiotherapy (with chemotherapy in advanced stages) vs surgery (with radiotherapy in advanced stages). Methods: A retrospective study on 50 patients with squamous cell cancer of the oropharynx treated by radiotherapy (with or without chemotherapy) at our institution between 1998 and2008 was carried out. The oncological and functional results were compared with patients with same cancer location and stage treated by surgery (with or without radiotherapy). In both groups, the patients were classified as follows: 10% Stage I, 12% Stage II, 16% Stage III, 48%Stage IVa and 14% Stage IVb. Results: The 5-year disease-specific survival was 33% in the radiotherapy group and 52% in the surgical group (P=.17). Five-year disease-specific survival for Stage I and II patients was 82% in the radiotherapy group and 70% in the surgical group. In Stage III and IV disease, 5-year disease specific survival was higher in the surgical group (47% vs 17%). The functional results were similar; anatomical and functional preservation of the larynx was higher in the radiotherapy group but the successful return to oral food intake was higher in the surgical group. Conclusions: The prognosis of squamous cell carcinoma of the oropharynx is poor. Oncological results in Stages I and II were similar for radiotherapy and surgical treatments. In advanced stages, the prognosis was better in patients treated by surgery with or without radiotherapy. Functional results were similar in both treatment modalities (AU)
Asunto(s)
Humanos , Carcinoma de Células Escamosas/terapia , Neoplasias Orofaríngeas/terapia , Calidad de Vida , Supervivencia sin Enfermedad , Radioterapia/estadística & datos numéricos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
INTRODUCTION AND OBJECTIVES: Squamous cell carcinomas of the oropharynx are aggressive tumours usually diagnosed at advanced stage. Their optimal treatment has not been established. The aim of this study was to compare the oncological and functional outcomes in patients with carcinomas of the oropharynx treated by radiotherapy (with chemotherapy in advanced stages) vs surgery (with radiotherapy in advanced stages). METHODS: A retrospective study on 50 patients with squamous cell cancer of the oropharynx treated by radiotherapy (with or without chemotherapy) at our institution between 1998 and 2008 was carried out. The oncological and functional results were compared with patients with same cancer location and stage treated by surgery (with or without radiotherapy). In both groups, the patients were classified as follows: 10% Stage I, 12% Stage II, 16% Stage III, 48% Stage IVa and 14% Stage IVb. RESULTS: The 5-year disease-specific survival was 33% in the radiotherapy group and 52% in the surgical group (P=.17). Five-year disease-specific survival for Stage I and II patients was 82% in the radiotherapy group and 70% in the surgical group. In Stage III and IV disease, 5-year disease-specific survival was higher in the surgical group (47% vs 17%). The functional results were similar; anatomical and functional preservation of the larynx was higher in the radiotherapy group but the successful return to oral food intake was higher in the surgical group. CONCLUSIONS: The prognosis of squamous cell carcinoma of the oropharynx is poor. Oncological results in Stages I and II were similar for radiotherapy and surgical treatments. In advanced stages, the prognosis was better in patients treated by surgery with or without radiotherapy. Functional results were similar in both treatment modalities.
Asunto(s)
Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirugía , Neoplasias Orofaríngeas/radioterapia , Neoplasias Orofaríngeas/cirugía , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Cetuximab , Quimioterapia Adyuvante , Cisplatino/uso terapéutico , Terapia Combinada , Supervivencia sin Enfermedad , Nutrición Enteral/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Neoplasias Laríngeas/tratamiento farmacológico , Neoplasias Laríngeas/patología , Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/cirugía , Masculino , Persona de Mediana Edad , Disección del Cuello , Recurrencia Local de Neoplasia/epidemiología , Estadificación de Neoplasias , Neoplasias Orofaríngeas/tratamiento farmacológico , Neoplasias Orofaríngeas/patología , Pronóstico , Calidad de Vida , Estudios Retrospectivos , Factores de Riesgo , Traqueotomía/estadística & datos numéricos , Resultado del TratamientoRESUMEN
BACKGROUND: A subset of lung cancer patients harbour EGFR somatic mutations in their tumours and are candidates for treatment with EGFR tyrosine kinase inhibitors. In a few cases EGFR mutations have also been found in the germ line, suggesting a role in lung carcinogenesis. Objetives of this study were: 1) To analyze the EGFR gene mutations in a population diagnosed with lung adenocarcinoma from Northern Spain. 2) To determine the frequency of a new germ-line mutation found in our laboratory as well as the frequency in our population of three other EGFR germ-line mutations detected by other authors. 3) To determine whether the novel mutation detected may have a functional effect on the EGFR protein. METHODS: Tumour DNA samples were obtained from frozen or paraffin embedded tumour tissues. Samples of DNA from peripheral blood cells were obtained from 912 individuals with lung cancer recruited from the CAPUA study 12, 477 unrelated healthy donor individuals and 32 individuals with other types of cancer. EGFR gene exons 18 to 21 were studied by direct standard dideoxy sequencing. Specific mutations were determined either by direct sequencing or by specific RFLP analysis. Cell lines were transfected with EGFR-mutant plasmids and analysed by western blot with antibodies specific for total or phosphorylated-EGFR. RESULTS: We found EGFR mutation in 12 of the 71 tumour samples (17%). One tumour contained two mutations. One mutation (p.R776G) was present as a germ line. Using an RFLP analysis, this mutation was not found in 954 alleles from healthy individuals studied, concluding that it is not a polymorphism. The mutation was not found either in genomic DNA from 912 lung cancer patients. Three additional EGFR germ-line mutations that were already described were not found in any of the studied samples. These observations show that EGFR mutated alleles are rare in the population. In vitro studies revealed that tyrosine autophosphorylation is enhanced in p.R776G-mutant EGFR when compared with wild-type EGFR. This enhanced autophosphorylation in the absence of ligand may be associated with a proliferative advantage. CONCLUSIONS: Germ-line mutations in EGFR are rare but may contribute to oncogenesis.
Asunto(s)
Adenocarcinoma/genética , Transformación Celular Neoplásica/genética , Receptores ErbB/genética , Mutación de Línea Germinal/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/metabolismo , Adenocarcinoma del Pulmón , Adulto , Anciano , Alelos , Animales , Secuencia de Bases , Células COS , Chlorocebus aethiops , Receptores ErbB/metabolismo , Exones/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Frecuencia de los Genes/genética , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo Genético , España , Adulto JovenRESUMEN
INTRODUCTION: Pegylated liposomal doxorubicin (PLD) is currently the reference treatment for platinum-resistant ovarian cancer. The combination of PLD and gemcitabine and the administration of gemcitabine at a fixed dose rate infusion (FDRI) seem to have additive activity in this disease setting. We have launched a phase Ib study with the combination of FDRI gemcitabine followed by PLD in recurrent ovarian cancer with a platinum-free interval of less than 1 year, with parallel pharmacokinetic and pharmacogenetic studies. METHODS: The starting dose of gemcitabine was 1500 mg/m², 10 mg/m² per minute, every 2 weeks (± 250 mg gemcitabine titration depending on toxicity), followed by PLD 35 mg/m² every 4 weeks. Gemcitabine pharmacokinetics and equilibrative nucleoside transporter 1, deoxycytidine kinase, and ribonucleotide reductase M1 gene expression levels were studied. RESULTS: Thirty-five patients were treated at 3 different dose levels (DL). Dose level 1 was not tolerated. Nonfrail patients continued to be treated at DL-1 (G 1250 mg/m² on day 1 and PLD 35 mg/m² on days 1 and 15). Of 10 evaluable nonfrail patients, 4 displayed dose-limiting toxicity. Frail patients were treated at DL-2 (G 1250 mg/m on day 1 and PLD 35 mg/m² on days 1 and 15). Of the 12 evaluable frail patients, 3 developed dose-limiting toxicity. Neutropenia, palmar-plantar erythrodysesthesia and stomatitis were the most common toxicities. The response rate was 42.8% (95% confidence interval [CI], 34.5%-51.1%), with 17.1% (6/35) complete responses and 25.7% (9/35) partial responses. The median progression-free survival was 7.7 months (95% CI, 2.2-13.1). The median overall survival was 13.9 months (95% CI, 9.4-18.4). The administration of PLD after gemcitabine did not influence gemcitabine pharmacokinetics or its metabolites. The addition of PLD to gemcitabine caused a larger and longer induction of the ribonucleotide reductase M1 gene. Patients with higher baseline levels of deoxycytidine kinase had longer progression-free survival. CONCLUSION: The recommended dose for a phase II study of patients with recurrent ovarian cancer having poor prognosis is PLD, 35 mg/m² on day 1, and gemcitabine, 1000 mg/m² on days 1 and 15 delivered at an FDRI of 10 mg/m per minute in 28-day cycles.
Asunto(s)
Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma Mucinoso/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cistadenocarcinoma Seroso/tratamiento farmacológico , Neoplasias Endometriales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Femenino , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Polietilenglicoles/administración & dosificación , Tasa de Supervivencia , Distribución Tisular , Resultado del Tratamiento , GemcitabinaRESUMEN
Topotecan, a semi-synthetic camptothecin analogue with topoisomerase I interaction, has shown to be an active agent in the treatment of advanced refractory lung cancer. This paper describes the authors' experience with this drug when used as a single agent in patients (pts) with advanced non-small cell lung cancer (NSCLC) refractory to platinum- and taxane-containing chemotherapy regimens. Thirty-five patients with NSCLC refractory to previous chemotherapy and KI ≥ 60% were included in the study. Their characteristics are as follows: median age of 52 years (range 43-69) and Karnofsky PS of 70 (60-80); 27 were male and 8 were female. Twenty-one (60%) patients had adenocarcinoma; eleven (31.4%), squamous cell, and three (8.5%), undifferentiated carcinoma. There was a median of two disease sites and two prior chemotherapy regimens. Topotecan was administered at a dose of 1.25 mg/m(2) I.V. daily for 5 days, repeated every 21 days until disease progression, maximal response, or intolerable toxicity. After 73 cycles, patients received a median of 2 treatment cycles (1-9). All patients except one were considered evaluable for toxicity; eight episodes (24%) of nausea/vomiting and two episodes (6%) of grade 1-2 asthenia, respectively, were reported. Four (12%) patients developed grade 1-2 anemia and two (6%) subjects suffered grade 3 anemia. Seven (21%) patients had grade 1-2 neutropenia and one (3%) presented grade 5 neutropenia. In 33 patients evaluable for activity of the 35 subjects included in the study; one (2.8%) presented a partial response; nine (25.7%) had stable disease, and 23 (65.7%) exhibited disease progression. Median time to progression and overall survival were 54 (12-210) and 70 (12-324) days, respectively. Intravenous topotecan at that dose and administration schedule displays scant activity in terms of response rate in individuals with advanced NSCLC previously treated with platinum and taxanes. The role and usefulness of chemotherapy in this setting warrants further investigation and confirmation through comparative studies.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Topoisomerasa I/uso terapéutico , Topotecan/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Progresión de la Enfermedad , Femenino , Humanos , Infusiones Intravenosas , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Compuestos de Platino/administración & dosificación , Estudios Prospectivos , Sobrevida , Taxoides/administración & dosificación , Inhibidores de Topoisomerasa I/efectos adversos , Topotecan/efectos adversos , Resultado del TratamientoRESUMEN
INTRODUCTION: For nearly the past two decades, cytokines (CKs) have been the only systemic treatment option available for advanced renal cell carcinoma (RCC). In recent years, tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity on this tumour. Our purpose is to describe one centre's experience with the use of CKs and TKIs in the treatment of patients with advanced RCC. MATERIALS AND METHODS: This study was designed as a retrospective chart review of RCC patients who were treated with CKs and/or TKIs in our department between July 1996 and June 2008. Efficacy and toxicity were assessed using World Health Organization (WHO) criteria. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall (OS) survival. RESULTS: Ninety-four patients were classified into three groups depending on the modality of treatment administered: 46 were treated with CKs alone and/or chemotherapy (27 with immunotherapy, one with chemotherapy and 18 with both), 28 with TKIs alone (25 with sunitinib and 13 with sorafenib) and 20 with TKIs in second-line treatment following failure with CKs (17 with sunitinib, eight with sorafenib, four with bevacizumab and one with lapatinib). The median age was 60 years in the CK group and 65 and 62, respectively, in TKI in first and second-line treatment groups. Eighty-five percent of patients treated with CKs and 75% in the TKI group in first-line treatment and 80% in second-line treatment were men. Overall, 89% of patients had favourable risk, and 11% had intermediate risk. All patients were considered evaluable for toxicity. The main grade 3-4 (%) toxicity was asthenia for both groups, (ten in TKIs and 15 in CKs). Other grade 1-2 toxicities were mucositis (39), bleeding (8), hypertension (19), skin toxicity (33) and hypothyroidism (12.5) associated with TKIs; and anaemia (33), cough (29), asthenia (39) and emesis (14) associated with CKs. The objective response rate among 80 patients evaluable for activity was 10.6% with CKs and 46.5% and 35%, respectively, with TKIs in first- and second-line treatments. Disease stabilisation with CKs was recorded at 59% of patients and with TKIs 25% and 50% in first- and second-line treatment groups, respectively. The median progression-free survival (PFS) with CKs was 122 days [95% confidence interval (CI) 82-162] and with TKIs 201 days (65-337) in the first and 346 days (256-436) in second-line treatment groups. The median overall survival (OS) was 229 days (142-316) and 2,074 days (1,152-2,996) for patients treated with CKs and TKIs. CONCLUSIONS: Our results are in line with the activity and survival rates previously reported in the literature regarding the use of TKIs for patients with advanced RCC in first- and second-line treatment, which has demonstrated an acceptable toxicity level.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Bencenosulfonatos/administración & dosificación , Bencenosulfonatos/efectos adversos , Bencenosulfonatos/uso terapéutico , Bevacizumab , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Quimioterapia Combinada/efectos adversos , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/uso terapéutico , Indoles/administración & dosificación , Indoles/efectos adversos , Indoles/uso terapéutico , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Interferón-alfa/uso terapéutico , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Interleucina-2/uso terapéutico , Estimación de Kaplan-Meier , Neoplasias Renales/mortalidad , Lapatinib , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/uso terapéutico , Pirroles/administración & dosificación , Pirroles/efectos adversos , Pirroles/uso terapéutico , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinazolinas/uso terapéutico , Estudios RetrospectivosAsunto(s)
Predisposición Genética a la Enfermedad/genética , Mutación , Paraganglioma/genética , Succinato Deshidrogenasa/genética , Adolescente , Adulto , Anciano , Salud de la Familia , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Linaje , Penetrancia , Adulto JovenRESUMEN
PURPOSE: Gastrointestinal stromal tumors (GIST) are a distinctive group of mesenchymal neoplasms of the gastrointestinal tract. The oncogene KIT has a central role in the pathogenesis of GIST, with c-kit receptor tyrosine kinase (KIT) protein expression being the gold standard in its diagnosis. The identification of GIST patients has become crucial, because the tyrosine kinase inhibitor Imatinib is effective in the treatment of this malignancy. However, a small set of GISTs remain unrecognized, because KIT protein expression is not always evident. The aim of this study was the identification of new markers for the differential diagnosis of GIST. EXPERIMENTAL DESIGN: By analyzing publicly available data from transcriptional profiling of sarcomas, we found that protein kinase C theta (PKC-theta), a novel PKC isotype involved in T-cell activation, is highly and specifically expressed in GIST. PKC-theta expression in GIST was confirmed by reverse transcription-PCR and Western blot. PKC-theta was analyzed by immunohistochemistry in a panel of 26 GIST, 12 non-GIST soft-tissue sarcomas, and 35 tumors from other histologies. RESULTS: We found that all of the GISTs expressed PKC-theta, whereas this protein was undetectable in other mesenchymal or epithelial tumors, including non-GIST KIT-positive tumors. PKC-theta immunoreactivity was also observed in interstitial cells of Cajal. CONCLUSIONS: Our results show that PKC-theta is easily detected by immunohistochemistry in GIST specimens and that it could be a sensitive and specific marker for the diagnosis of this malignancy.
Asunto(s)
Neoplasias Gastrointestinales/enzimología , Isoenzimas/biosíntesis , Mesodermo/enzimología , Proteína Quinasa C/biosíntesis , Células del Estroma/enzimología , Benzamidas , Western Blotting , Regulación de la Expresión Génica , Humanos , Mesilato de Imatinib , Inmunohistoquímica , Neoplasias/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Piperazinas/farmacología , Isoformas de Proteínas , Proteína Quinasa C-theta , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/biosíntesis , Pirimidinas/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sarcoma/metabolismo , Linfocitos T/metabolismo , Transcripción GenéticaRESUMEN
Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is active in the treatment of non-small cell lung cancer (NSCLC). In this report we describe our experience with this drug when used as a single agent in patients with advanced NSCLC refractory to chemotherapy with platinum and taxanes. Nineteen NSCLC patients (thirteen males and six females; 53% adenocarcinoma and 26% squamous cell carcinoma) with a median age of 52 years (range 34-71) and a Karnofsky performance status of 60% (60-80%) were included in the study. At baseline, the patients had a median of two disease sites and had been treated with a median of two prior regimens. Irinotecan was given at a dose of 100 mg/m(2) i.v.) weekly for 4 weeks followed by 1 week of rest. A total of 123 weekly infusions were administered, and each patient received a median of 4 weeks of treatment (range 1-32). All patients were evaluated by intention-to-treat analysis for efficacy and safety. Main toxicities reported were grade 3 neutropenia (10% of patients), diarrhea (10% of patients), and grade 4 thrombocytopenia (5% of patients). The overall clinical response rate was 16% (95% CI: 8-24) with three partial responses and 9 (47%) patients with stable disease. The median time to progression and the median survival time were 7 and 15 weeks, respectively. In conclusion, weekly irinotecan showed antitumoral activity and minimum toxicity in NSCLC patients refractory to platinum and taxanes.