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1.
Ann Oncol ; 34(3): 251-261, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36535566

RESUMEN

BACKGROUND: Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, programmed death ligand 1 (PD-L1)-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented. PATIENTS AND METHODS: KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1 : 1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary endpoint was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population. RESULTS: Between 5 May 2016 and 28 May 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cut-off (30 November 2020) was 45.1 months (interquartile range, 39.0-48.8 months). Median OS was 17.2 months [95% confidence interval (CI) 11.7-22.9 months] with pembrolizumab and 15.3 months (95% CI 10.9-18.1 months) with chemotherapy [hazard ratio, 0.90 (95% CI 0.67-1.19; P = 0.2262)]. Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage). CONCLUSION: Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events.


Asunto(s)
Neoplasias Nasofaríngeas , Platino (Metal) , Humanos , Neoplasias Nasofaríngeas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados , Docetaxel , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
2.
ESMO Open ; 7(3): 100511, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35688062

RESUMEN

BACKGROUND: KRAS gene mutations can predict prognosis and treatment response in patients with metastatic colorectal cancer (mCRC). METHODS: We undertook a meta-analysis of three randomized, placebo-controlled trials (RECOURSE, TERRA and J003) to investigate the impact of KRAS mutations in codons 12 or 13 on overall survival (OS) and progression-free survival in patients receiving trifluridine/tipiracil (FTD/TPI) for refractory mCRC. RESULTS: A total of 1375 patients were included, of whom 478 had a KRAS codon 12 mutation and 130 had a KRAS codon 13 mutation. In univariate analyses, the absence of a KRAS codon 12 mutation was found to significantly increase the OS benefit of FTD/TPI relative to placebo compared with the presence of the mutation {hazard ratio (HR), 0.62 [95% confidence interval (CI): 0.53-0.72] versus 0.86 (0.70-1.05), respectively; interaction P = 0.0206}. Multivariate analyses showed that taking confounding factors into account reduced the difference in treatment effect between the presence and the absence of KRAS codon 12 mutations, confirming that treatment benefit was maintained in patients with [HR, 0.73 (95% CI: 0.59-0.89)] and without [HR, 0.63 (95% CI: 0.54-0.74)] codon 12 mutations (interaction P = 0.2939). KRAS mutations in codon 13 did not reduce the OS benefit of FTD/TPI relative to placebo, and, furthermore, KRAS mutations at either codon 12 or codon 13 did not affect the progression-free survival benefit. CONCLUSIONS: Treatment with FTD/TPI produced a survival benefit, relative to placebo, regardless of KRAS codon 12 or 13 mutation status in patients with previously treated mCRC.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Demencia Frontotemporal , Codón/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Demencia Frontotemporal/inducido químicamente , Demencia Frontotemporal/tratamiento farmacológico , Demencia Frontotemporal/genética , Humanos , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Pirrolidinas , Ensayos Clínicos Controlados Aleatorios como Asunto , Timina , Trifluridina/farmacología , Trifluridina/uso terapéutico , Uracilo/uso terapéutico
3.
Clin Transl Oncol ; 22(7): 1117-1125, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31754936

RESUMEN

BACKGROUND: Non-tumor-derived circulating DNA (nt-cirDNA) of advanced non-small cell lung cancer (NSCLC), with unclear origination, is associated with prognosis. We hypothesized that a part of nt-cirDNA release from CD3 or CD8 tumor-infiltrating lymphocytes (TILs) could have clinical implications. METHOD: To investigate the feasibility of T-cell-derived circulating DNA (T-cirDNA) detection, real-time PCR with Taqman assay-specific rearranged TCRß CDR3 region was conducted in plasma of 103 advanced NSCLC. CD3 and CD8-specific immunohistochemistry from biopsy specimen, was reviewed by one blinded pathologist to the T-cirDNA results. Prognostic impact including demographic characteristics was integrated into the model. RESULTS: Circulating DNA was detectable in 100 patients with median of 4 ng ml-1, while median of plasma T-cirDNA was 1.71 pg ml-1. Median %ratio of T-cirDNA/cirDNA was 0.02%. T-cirDNA was categorized by %ratio of T-cirDNA/cirDNA as undetectable, low (≤ 1%) and high (> 1%). Paradoxical prognostic impact of T-cirDNA/cirDNA was observed. Undetectable and high T-cirDNA/cirDNA translated to independent favorable prognostic outcome, HR of 0.54 [95% CI 0.30-0.96] and 0.41 [95% CI 0.21-0.80], respectively. 43 patients were assessed for CD3/CD8 TILs and PD-L1. High intratumoral CD3/CD8 TILs but not stromal CD3 TILs was correlated with high T-cirDNA/cirDNA representing active T-lymphocyte activity to eliminate cancer cells. While the prognosis of undetectable T-cirDNA/cirDNA, represents inactivated naïve T-cell, was determined by the presence of EGFR mutation and had long durable response of EGFR inhibitors. CONCLUSION: T-cirDNA could be a novel biomarker representing adaptive immune resistance in NSCLC patients. Further exploration as a predictive biomarker for EGFR inhibitors in setting of EGFR mutation might be warranted.


Asunto(s)
Adenocarcinoma/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Ácidos Nucleicos Libres de Células/sangre , Neoplasias Pulmonares/sangre , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos T/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Complejo CD3 , Antígenos CD8 , Linfocitos T CD8-positivos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Ácidos Nucleicos Libres de Células/metabolismo , Femenino , Estado Funcional , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia
4.
Oral Oncol ; 49(9): 872-877, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23830839

RESUMEN

Head and neck cancer (HNC) is a disease of the upper aerodigestive tract and is one of the most frequently diagnosed cancers worldwide. A high rate of cancers involving the head and neck are reported across the Asian region, with notable variations between countries. Disease prognosis is largely dependent on tumor stage and site. Patients with early stage disease have a 60-95% chance of cure with local therapy. Early diagnosis and appropriate treatment are important to increase the likelihood of cure and survival. However, the majority of patients present with locally advanced disease and require multimodality treatment. This necessitates, a multidisciplinary approach which is essential to make appropriate treatment decisions, particularly with regards to tolerability, costs, available infrastructure and quality of life issues. Unfortunately, majority of the studies that dictate current practice have been developed in the west where diseases biology, patient population and available infrastructure are very different from those in the Asian continent. With this in mind an expert panel of Head and Neck Oncologists was convened in May 2012 to review the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) clinical practice guidelines and develop practical recommendations on the applicability of these guidelines on the management of head and neck cancer for Asian patients. The objective of this review and consensus meeting was to suggest revisions, to account for potential differences in demographics and resources, to the NCCN and ESMO guidelines, to better reflect current clinical management of head and neck cancer within the Asian region for health care providers. These recommendations, which reflect best clinical practice within Asia, are expected to benefit practitioners when making decisions regarding optimal treatment strategies for their patients.


Asunto(s)
Consenso , Neoplasias de Cabeza y Cuello/terapia , Guías de Práctica Clínica como Asunto , Asia , Neoplasias de Cabeza y Cuello/fisiopatología , Humanos , Pronóstico
5.
Asia Pac J Clin Oncol ; 6(3): 155-60, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20887495

RESUMEN

AIM: The aim of the present study was to compare the efficacy of 200 mg versus 400 mg daily of pyridoxine in preventing or delaying the onset of palmar-plantar erythrodysesthesia (PPE) in capecitabine-treated patients. METHODS: Patients with histologically confirmed breast cancer or colorectal cancer receiving single agent capecitabine started at 2000 to 2500 mg/m(2) daily from day 1 to 14 every 3 weeks were randomly assigned to receive 200 mg or 400 mg daily of pyridoxine for PPE prophylaxis. The primary endpoint was the reduction of incidence of grade 2 or greater PPE. Secondary endpoints were reduction of severe PPE and prolongation of time to development of grade 2 or greater PPE. RESULTS: There were 56 patients in this study. The baseline characteristics were generally similar in both groups. The high dose arm had less PPE than the low dose arm (11 of 28 or 39% vs 20 of 28 or 71%, relative risk = 0.26 [0.08, 0.79], P = 0.031). Grade III PPE developed in 3 of 28 (10.7%) versus none in patients receiving 200 mg versus 400 mg pyridoxine, respectively (relative risk 2.12 [1.594, 2.819], P = 0.24). High dose pyridoxine had a longer time to development of grade 2 or greater PPE compared to the low dose arm, 87 days versus 62 days. The 400 mg pyridoxine group had, however, a worsened tumor response and tended to have greater tumor treatment failure and shorter time to treatment failure. CONCLUSION: With the limitation of sample size in this study, there was a trend to improve PPE incidence and time to event with a higher dose of pyridoxine. Further validation of these results in a larger population is warranted.


Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Desoxicitidina/análogos & derivados , Eritema/prevención & control , Fluorouracilo/análogos & derivados , Piridoxina/administración & dosificación , Complejo Vitamínico B/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Capecitabina , Neoplasias Colorrectales/tratamiento farmacológico , Desoxicitidina/efectos adversos , Relación Dosis-Respuesta a Droga , Eritema/inducido químicamente , Femenino , Fluorouracilo/efectos adversos , Dermatosis del Pie/inducido químicamente , Dermatosis del Pie/prevención & control , Dermatosis de la Mano/inducido químicamente , Dermatosis de la Mano/prevención & control , Humanos , Masculino , Persona de Mediana Edad
6.
Cancer Lett ; 239(2): 292-7, 2006 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-16243431

RESUMEN

Recent reports have suggested influences of racial difference on the frequency of mutation of EGFR in lung cancer. We therefore sought to characterize the frequency and pattern of mutation of EGFR in lung adenocarcinoma in Thai patients. Overall, EGFR catalytic domain mutations were detected in 35/61 (57.4%). We found 29/60 (48.3%) of exon 19 deletions, 5/54 (9.3%) of exon 21 point mutations, and 1/54 (1.9%) of double-mutation of both exons. The presence of these mutations was significantly associated with non-smoking habit. In summary, we report a strikingly high prevalence of mutation of EGFR in Thai lung adenocarcinoma, which may explain the high response rate to the treatment with TKI among Asian populations.


Asunto(s)
Adenocarcinoma/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Secuencia de Aminoácidos , Secuencia de Bases , Exones , Humanos , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Tailandia
7.
Brain Res Mol Brain Res ; 95(1-2): 162-6, 2001 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-11687288

RESUMEN

Mammalian Scratch (Scrt) is a Snail family zinc finger transcription factor that is specifically expressed in newly differentiating, post-mitotic central nervous system neurons. While Scrt-related genes appear essential for invertebrate neurogenesis, the role of Scrt in mammalian neural development is unknown. In this study, we found that neural differentiation of multipotent mouse P19 embryonal carcinoma cells by retinoic acid led to the appearance of Scrt together with neuron-specific class III beta-tubulin (Tuj1), following the earlier elaboration of Mash1. Transient co-transfection in P19 cells with either Mash1 or NeuroD2 plus E12 also induced Scrt gene expression. Moreover, overexpression of Scrt alone was sufficient to confer Tuj1 immunoreactivity and neuronal morphology in a subset of P19 cells. Scrt thus appears to function downstream of proneural bHLH proteins in promoting mammalian neural differentiation in this model system.


Asunto(s)
Neuronas/citología , Factores de Transcripción/fisiología , Dedos de Zinc , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Diferenciación Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Electroforesis en Gel de Poliacrilamida , Técnica del Anticuerpo Fluorescente , Immunoblotting , Ratones , Neuronas/metabolismo , Neuropéptidos/genética , Neuropéptidos/metabolismo , Factores de Transcripción TCF , Proteína 1 Similar al Factor de Transcripción 7 , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transfección , Tretinoina/farmacología , Células Tumorales Cultivadas
8.
Cancer Res ; 61(7): 3200-5, 2001 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-11306509

RESUMEN

Among the various forms of human lung cancer, small cell lung cancer (SCLC) exhibits a characteristic neuroendocrine (NE) phenotype. Neural and NE differentiation in SCLC depend, in part, on the action of the basic-helix-loop-helix (bHLH) transcription factor human achaete-scute homologue-1 (hASH1). In nervous system development, the Notch signaling pathway is a critical negative regulator of bHLH factors, including hASH1, controlling cell fate commitment and differentiation. To characterize Notch pathway function in SCLC, we explored the consequences of constitutively active Notch signaling in cultured SCLC cells. Recombinant adenoviruses were used to overexpress active forms of Notch1, Notch2, or the Notch effector protein human hairy enhancer of split-1 (HES1) in DMS53 and NCI-H209 SCLC cells. Notch proteins, but not HES1 or control adenoviruses, caused a profound growth arrest, associated with a G1 cell cycle block. We found up-regulation of p21(waf1/cip1) and p27kip1 in concert with the cell cycle changes. Active Notch proteins also led to dramatic reduction in hASH1 expression, as well as marked activation of phosphorylated extracellular signal-regulated kinase (ERK)1 and ERK2, findings that have been shown to be associated with cell cycle arrest in SCLC cells. These data suggest that the previously described function of Notch proteins as proto-oncogenes is highly context-dependent. Notch activation, in the setting of a highly proliferative hASH1-dependent NE neoplasm, can be associated with growth arrest and apparent reduction in neoplastic potential.


Asunto(s)
Carcinoma de Células Pequeñas/patología , Proteínas de Ciclo Celular , Proteínas de Homeodominio , Neoplasias Pulmonares/patología , Proteínas de la Membrana/fisiología , Receptores de Superficie Celular/fisiología , Transducción de Señal/fisiología , Proteínas Supresoras de Tumor , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Ciclo Celular/fisiología , División Celular/fisiología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Ciclinas/biosíntesis , Ciclinas/genética , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Activación Enzimática , Fase G1/fisiología , Secuencias Hélice-Asa-Hélice , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas de la Membrana/biosíntesis , Proteínas Asociadas a Microtúbulos/biosíntesis , Proteínas Asociadas a Microtúbulos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Musculares/fisiología , Receptor Notch1 , Receptor Notch2 , Receptores de Superficie Celular/biosíntesis , Factor de Transcripción HES-1 , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Regulación hacia Arriba
9.
Proc Natl Acad Sci U S A ; 98(7): 4010-5, 2001 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-11274425

RESUMEN

Members of the Snail family of zinc finger transcription factors are known to play critical roles in neurogenesis in invertebrates, but none of these factors has been linked to vertebrate neuronal differentiation. We report the isolation of a gene encoding a mammalian Snail family member that is restricted to the nervous system. Human and murine Scratch (Scrt) share 81% and 69% identity to Drosophila Scrt and the Caenorhabditis elegans neuronal antiapoptotic protein, CES-1, respectively, across the five zinc finger domain. Expression of mammalian Scrt is predominantly confined to the brain and spinal cord, appearing in newly differentiating, postmitotic neurons and persisting into postnatal life. Additional expression is seen in the retina and, significantly, in neuroendocrine (NE) cells of the lung. In a parallel fashion, we detect hScrt expression in lung cancers with NE features, especially small cell lung cancer. hScrt shares the capacity of other Snail family members to bind to E-box enhancer motifs, which are targets of basic helix--loop--helix (bHLH) transcription factors. We show that hScrt directly antagonizes the function of heterodimers of the proneural bHLH protein achaete-scute homolog-1 and E12, leading to active transcriptional repression at E-box motifs. Thus, Scrt has the potential to function in newly differentiating, postmitotic neurons and in cancers with NE features by modulating the action of bHLH transcription factors critical for neuronal differentiation.


Asunto(s)
Proteínas de Drosophila , Neuronas/metabolismo , Proteínas Represoras/aislamiento & purificación , Factores de Transcripción/aislamiento & purificación , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Secuencia de Consenso/genética , Proteínas de Unión al ADN/genética , Drosophila , Silenciador del Gen , Genes Reporteros , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Sistemas Neurosecretores/metabolismo , Proteínas Represoras/genética , Homología de Secuencia de Aminoácido , Caracoles/genética , Factores de Transcripción TCF , Proteína 1 Similar al Factor de Transcripción 7 , Factores de Transcripción/genética , Transcripción Genética , Activación Transcripcional , Células Tumorales Cultivadas
10.
J Med Assoc Thai ; 83(2): 123-8, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10710880

RESUMEN

Fifteen patients with histologically proven metastatic or unresectable renal cell carcinoma were enrolled for a phase II trial of Interferon-alpha 2b (> or = 6 x 10(6) U/m2) plus megestrol acetate (160 mg/day). A response rate of 14.3 per cent was achieved in this study. We observed weight gain (median 3.2 kilogram; range 1.1 to 6.9) in 5 patients, and stable weight in 5 of the 14 patients who completed the protocol. Weight gain occurred regardless of extent of metastasis or response to interferon. Our data suggest a possible role for megestrol acetate in alleviating anorexia and weight loss in patients with renal cell carcinoma undergoing interferon treatment. Further clinical trials are clearly warranted.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Acetato de Megestrol/administración & dosificación , Anciano , Carcinoma de Células Renales/mortalidad , Femenino , Humanos , Interferón alfa-2 , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Tasa de Supervivencia , Resultado del Tratamiento
11.
Int J Cancer ; 83(2): 210-4, 1999 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-10471529

RESUMEN

Our main purpose was to identify tumor suppressor gene loci on chromosome 13 responsible for nasopharyngeal cancer (NPC) development by analyzing loss of heterozygosity (LOH) and RB protein expression in paraffin embedded tissues. Normal and tumor DNA were extracted from microdissected samples, and their whole genomes were amplified using degenerate oligonucleotide primers. The polymerase chain reaction (PCR) products were analyzed by repeated amplification using primers derived from 16 microsatellite regions spanning the long arm of this chromosome. Among 50 informative cases, LOH was observed in 44 tumors. Thirty-one tumors displayed partial loss and provided an informative basis for detailed deletion mapping. Three minimal regions of loss were delineated; the first flanked by D13S120 and D13S219, the second by D13S126 and D13S119, and the third by D13S137 and 13qter. These 3 regions were linked to BRCA2 on 13q12, RB1 on 13q14, and 13q14.3-ter, respectively. Seven and 4 cases showed LOH either on 13q12 or 13q14, respectively. Nineteen cases showed LOH of both loci separately. One NPC displayed 13q12 and 13q14.3-ter LOH. RB protein expression was detectable in 76% of the cases. Ten out of 15 cases with the allelic losses limited to 13q14 showed RB protein expression. Contrasting that, 6 out of 7 cases devoid of RB protein expressions showed 13q14LOH. In conclusion, 13qLOH, involving 3 tumor suppressor gene loci, appears to be a frequent genetic event occurring during NPC development. However, other tumor suppressor genes besides RB1, may be responsible for the majority of 13q14LOH.


Asunto(s)
Alelos , Cromosomas Humanos Par 13 , Pérdida de Heterocigocidad , Neoplasias Nasofaríngeas/genética , Adulto , Anciano , Anciano de 80 o más Años , Mapeo Cromosómico , ADN de Neoplasias/análisis , ADN de Neoplasias/genética , Femenino , Humanos , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Adhesión en Parafina , Proteína de Retinoblastoma/biosíntesis , Proteína de Retinoblastoma/genética
12.
Int J Cancer ; 78(2): 153-6, 1998 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-9754644

RESUMEN

The main objective of this study was to determine the precise frequency of chromosome 14q loss of heterozygosity in nasopharyngeal carcinomas and to define its minimal deletion regions. Thirty-nine tumors were selected for PCR-based deletion mapping using 19 microsatellite polymorphic markers spanning the long arm of this chromosome. Loss of heterozygosity for at least one marker was observed in 29 (74.4%) tumors, while 24 of these tumors displayed partial loss and provided an informative basis for detailed deletion mapping. Three minimal regions of loss were delineated, the first defined by markers D14S278 and D14S288, the second being between D14S51 and the telomere. These data confirmed 2 potential tumor-suppressor-gene loci at 14q12-13 and 14q32. Interestingly, the third region of loss was located at the T-cell-receptor delta-chain locus. This may reflect another tumor-suppressor-gene locus at 14q11.2, or may be the consequence of a specific genomic rearrangement of this region. In addition, these allelic losses occurred with high frequency in all tumor grades and stages and in all histological sub-types. These findings suggest that the genetic alteration of chromosome 14 is common and crucial during nasopharyngeal-carcinoma development.


Asunto(s)
Cromosomas Humanos Par 14 , Pérdida de Heterocigocidad , Neoplasias Nasofaríngeas/genética , Alelos , Reordenamiento Génico , Genes Codificadores de la Cadena delta de los Receptores de Linfocito T , Genes Supresores de Tumor , Humanos
13.
Br J Cancer ; 78(7): 933-9, 1998 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9764586

RESUMEN

The purpose of this study was to define a correlation between telomerase activity and human papillomavirus (HPV) in normal control tissue and in benign, premalignant and malignant cervical lesions. Telomerase activity was detectable in 33 out of 34 cases of squamous-cell carcinoma, five out of six cases of microinvasive carcinoma, 8 out of 20 cases and two out of six cases of high- and low-grade squamous intraepithelial lesions (SILs) respectively. The higher frequency of positive telomerase in invasive carcinoma compared with SILs was observed in both HPV-associated and non-associated groups. Whereas 92.6% of HPV-positive and 100% of HPV-negative invasive lesions expressed telomerase, only 50% of HPV-positive and 25% of HPV-negative SILs did. Interestingly, telomerase activity was also detectable in 13 out of 28 cases of benign lesions regardless of the presence of HPV. In conclusion, there may be two roles of telomerase in the cervix. The first one would present in benign lesions; the second is associated with cancer development and activated during the late stage of multistep carcinogenesis in both HPV-positive and -negative groups.


Asunto(s)
Proteínas de Neoplasias/metabolismo , Papillomaviridae/aislamiento & purificación , Lesiones Precancerosas/enzimología , Lesiones Precancerosas/virología , Telomerasa/metabolismo , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/virología , Carcinoma in Situ/enzimología , Carcinoma in Situ/virología , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/virología , Femenino , Humanos , Enfermedades del Cuello del Útero/enzimología , Enfermedades del Cuello del Útero/virología
14.
Am J Clin Oncol ; 21(4): 386-91, 1998 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-9708639

RESUMEN

Primary hepatocellular carcinoma (HCC) is a common malignancy with a dismal prognosis; new modalities of treatment as alternatives to surgery have been developed for unresectable patients. The authors obtain baseline data for the natural history of HCC so that the efficacy of new treatments may be evaluated. A retrospective study of 157 untreated patients with tissue-proven or serodiagnosed HCC was conducted. Clinical characteristics including laboratory investigation, treatment received, survival from the time of diagnosis, and prognostic factors were evaluated. There were 129 men and 28 women (ratio, 4.6:1). Median age was 50.9 years (range, 14.1-85.3 years). The most common symptoms and signs were weight loss (68.2%), abdominal fullness (62.5%), abdominal pain (51.6%), hepatomegaly (73.7%), ascites (45.2%), and jaundice (40.6%). Eighteen percent had extrahepatic metastases of which the lungs were the most common site. Seventy percent were hepatitis B virus related. Overall median survival was 8.7 weeks after the time of diagnosis. Survivals by stages were: TNM II, 16.6 weeks; TNM III, 7.3 weeks; TNM IVA, 9.7 weeks; TNM IVB, 7.6 weeks; Okuda II, 10.7 weeks; and Okuda III, 7.3 weeks. Multivariate analysis revealed serum total bilirubin and albumin as independent prognostic factors of survival. Common causes of death were upper gastrointestinal hemorrhage (34.1%), cancer-related causes (cachexia, HCC rupture, metastatic disease, 31.8%), and hepatic failure (25.0%). Patients with HCC were diagnosed at late stages of their disease and the advanced nature of the tumor precluded effective therapy. Earlier tumor detection at a time when patients are better candidates for treatment may be aided by an active surveillance program of high risk groups.


Asunto(s)
Carcinoma Hepatocelular/fisiopatología , Neoplasias Hepáticas/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/mortalidad , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia
16.
Clin Cancer Res ; 4(3): 665-9, 1998 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9533535

RESUMEN

This study evaluated Epstein-Barr virus (EBV) DNA in sera of 42 patients with nasopharyngeal carcinoma (NPC) and 82 healthy individuals who had been infected previously with EBV. Thirteen of 42 NPC samples were positive for EBV DNA in their sera, whereas all 82 normal controls were negative. In addition, EBV typing between primary tumors and sera showed identical results, suggesting that serum EBV DNA represented tumor DNA. To evaluate the importance of the serum NPC DNA, clinical data and tumor phenotypes including age, sex, WHO type, EBV type, stage, tumor invasion, metastasis, and apoptosis were correlated with serum EBV DNA, and only apoptosis was found statistically significant. In conclusion, EBV DNA was detectable in the serum of some patients with NPC, represented tumor DNA, and might have clinical implications in the future.


Asunto(s)
ADN Viral/sangre , Herpesvirus Humano 4/aislamiento & purificación , Neoplasias Nasofaríngeas/virología , Adulto , Factores de Edad , Apoptosis , Fragmentación del ADN , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/sangre , Neoplasias Nasofaríngeas/patología , Invasividad Neoplásica , Metástasis de la Neoplasia , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Valores de Referencia
17.
J Clin Lab Anal ; 12(1): 41-6, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9484668

RESUMEN

We evaluated the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) given after myelosuppressive chemotherapy in 15 cancer patients. No severe neutropenia (absolute neutrophil count, ANC < 0.5 x 10(3)/microL) was noticed in 10 rhG-CSF primary prophylactic patients, but was noticed in two of five rhG-CSF secondary prophylactic patients. Neutrophilia characterized by shift to the left occurred within 24 hours after starting rhG-CSF prophylaxis. Thereafter, conversion to normal level occurred within 24 hours. The peak of neutrophilia occurred earlier in the primary group than in the secondary prophylactic group. The detection of myeloperoxidase (MPO) using flow cytochemistry blood autoanalyzer (TechniconR H * 1) was evaluated as mean peroxidase index (MPXI). Leukocyte alkaline phosphatase (LAP) using the method of Kaplow (Am J Clin Pathol 39:439-449, 1963) was recorded as LAP score. There was a statistically significant elevation of MPXI in the primary group over the secondary prophylactic patients. The LAP activity was in normal range. There was a slightly decreased red blood cell (RBC) count, hemoglobin (Hb), and platelet count. In conclusion, rhG-CSF induced neutrophilia with efficient enzymatic activity. These findings demonstrate the value of rhG-CSF in patients receiving chemotherapy. MPXI and early neutrophilia may serve as a potential biomarker of therapeutic efficacy of rhG-CSF.


Asunto(s)
Antineoplásicos/efectos adversos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Leucocitosis/prevención & control , Neutrófilos/efectos de los fármacos , Peroxidasa/metabolismo , Adulto , Anciano , Biomarcadores , Eritrocitos/efectos de los fármacos , Femenino , Humanos , Leucocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes
18.
Br J Cancer ; 76(6): 770-6, 1997.
Artículo en Inglés | MEDLINE | ID: mdl-9310244

RESUMEN

Nasopharyngeal carcinoma is a subset of head and neck squamous cell cancers with unique endemic distribution and aetiological co-factors. Epstein-Barr virus has been revealed to be an important aetiological factor for most nasopharyngeal carcinomas. Nevertheless, additional genetic alterations may be involved in their development and progression. The aim of this study was to determine the likely chromosomal locations of tumour-suppressor genes related to Epstein-Barr virus-associated nasopharyngeal carcinoma. Fifty-six microsatellite polymorphic markers located on every autosomal arm were used to estimate the incidence of loss of heterozygosity in 27 Epstein-Barr virus-associated nasopharyngeal carcinomas. High frequencies of allelic loss were observed on chromosome 3p (75.0%) and 9p (87.0%). Chromosome 9q, 11q, 13q and 14q displayed loss in over 50%, while chromosome 3q, 6p, 16q, 19q and 22q exhibited loss in 35-50%. Furthermore, several other chromosomal arms demonstrated allelic loss in 20-35%. Additionally, 1 of the 27 cases showed microsatellite instability at multiple loci. These findings provide evidence of multiple genetic alterations during cancer development and clues for further studies of tumour-suppressor genes in Epstein-Barr virus-associated nasopharyngeal carcinoma.


Asunto(s)
Carcinoma/genética , Infecciones por Herpesviridae/genética , Neoplasias Nasofaríngeas/genética , Proteínas Supresoras de Tumor , Infecciones Tumorales por Virus/genética , Moléculas de Adhesión Celular/genética , Mapeo Cromosómico , Receptor DCC , ADN de Neoplasias/genética , ADN Viral/genética , Herpesvirus Humano 4 , Heterocigoto , Humanos , Queratinas/genética , Repeticiones de Microsatélite , Receptores de Superficie Celular , Eliminación de Secuencia
19.
J Med Assoc Thai ; 79 Suppl 1: S65-70, 1996 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9071069

RESUMEN

In order to demonstrate and define possible tumor suppressor gene loci on chromosome 11 associated with NPC, we used 7 STR to test for LOH on 25 NPC samples. LOH was detected in 46 per cent of cases. Most LOH loci were clustered on the long arm. Further study demonstrated 22 per cent and 45.5 per cent of cases with LOH on 11q13 and 11q23 respectively.


Asunto(s)
Cromosomas Humanos Par 11/genética , Herpesvirus Humano 4 , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/virología , Alelos , Cartilla de ADN , ADN de Neoplasias/aislamiento & purificación , ADN Viral/aislamiento & purificación , Infecciones por Herpesviridae/genética , Herpesvirus Humano 4/genética , Heterocigoto , Humanos , Reacción en Cadena de la Polimerasa , Secuencias Repetitivas de Ácidos Nucleicos , Infecciones Tumorales por Virus/genética
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