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INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has caused extensive disruption of public health worldwide. There were reports of COVID-19 patients having multiple complications. This study investigated COVID-19 from a genetic perspective. METHODS: We conducted RNA sequencing (RNA-Seq) analysis of respiratory tract samples from 24 patients with COVID-19. Eight patients receiving mechanical ventilation or extracorporeal membrane oxygenation were regarded as severe cases; the remaining 16 patients were regarded as non-severe cases. After quality control, statistical analyses were performed by logistic regression and the Kolmogorov-Smirnov test to identify genes associated with disease severity. RESULTS: Six genes were associated with COVID-19 severity in both statistical tests, namely RPL15, BACE1-AS, CEPT1, EIF4G1, TMEM91, and TBCK. Among these genes, RPL15 and EIF4G1 played roles in the regulation of mRNA translation. Gene ontology analysis showed that the differentially expressed genes were mainly involved in nervous system diseases. CONCLUSION: RNA sequencing analysis showed that severe acute respiratory syndrome coronavirus 2 infection is associated with the overexpression of genes involved in nervous system disorders.
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COVID-19 , Humanos , COVID-19/genética , Secretasas de la Proteína Precursora del Amiloide , SARS-CoV-2/genética , Hong Kong/epidemiología , Ácido Aspártico Endopeptidasas , Análisis de Secuencia de ARNRESUMEN
BACKGROUND: Quantitative measurement of plasma Epstein-Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients. PATIENTS AND METHODS: Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA. RESULTS: The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS. CONCLUSION: NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , ADN Viral/genética , Herpesvirus Humano 4/genética , Humanos , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/terapia , Recurrencia Local de Neoplasia/genética , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Medición de RiesgoRESUMEN
BACKGROUND: Early-stage nasopharyngeal carcinoma (NPC) evades detection when the primary tumor is hidden from view on endoscopic examination. Therefore, in a prospective study of subjects being screened for NPC using plasma Epstein-Barr virus (EBV) DNA, we conducted a study to investigate whether magnetic resonance imaging (MRI) could detect endoscopically occult NPC. PATIENTS AND METHODS: Participants with persistently positive EBV DNA underwent endoscopic examination and biopsy when suspicious for NPC, followed by MRI blinded to the endoscopic findings. Participants with a negative endoscopic examination and positive MRI were recalled for biopsy or surveillance. Diagnostic performance was assessed by calculating sensitivity, specificity and accuracy, based on the histologic confirmation of NPC in the initial study or in a follow-up period of at least two years. RESULTS: Endoscopic examination and MRI were performed on 275 participants, 34 had NPC, 2 had other cancers and 239 without cancer were followed-up for a median of 36 months (24-60 months). Sensitivity, specificity and accuracy were 76.5%, 97.5% and 94.9%, respectively, for endoscopic examination and 91.2%, 97.5% and 96.7%, respectively, for MRI. NPC was detected only by endoscopic examination in 1/34 (2.9%) participants (a participant with stage I disease), and only by MRI in 6/34 (17.6%) participants (stage I = 4, II = 1, III = 1), two of whom had stage I disease and follow-up showing slow growth on MRI but no change on endoscopic examination for 36 months. CONCLUSION: MRI has a complementary role to play in NPC detection and can enable the earlier detection of endoscopically occult NPC.
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Infecciones por Virus de Epstein-Barr/diagnóstico , Carcinoma Nasofaríngeo/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , Adulto , ADN Viral/sangre , ADN Viral/genética , Detección Precoz del Cáncer/métodos , Endoscopía/métodos , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/virología , Estudios de Seguimiento , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/diagnóstico por imagen , Carcinoma Nasofaríngeo/cirugía , Carcinoma Nasofaríngeo/virología , Neoplasias Nasofaríngeas/diagnóstico por imagen , Neoplasias Nasofaríngeas/cirugía , Neoplasias Nasofaríngeas/virología , Pronóstico , Estudios Prospectivos , Carga ViralRESUMEN
Three epidemic waves of human influenza A(H7N9) were documented in several different provinces in China between 2013 and 2015. With limited understanding of the potential for human-to-human transmission, it was difficult to implement control measures efficiently or to inform the public adequately about the application of interventions. In this study, the human-to-human transmission rate for the epidemics that occurred between 2013 and 2015 in Zhejiang Province, China, was analysed. The reproduction number (R), a key indicator of transmission intensity, was estimated by fitting the number of infections from poultry to humans and from humans to humans into a mathematical model. The posterior mean R for human-to-human transmission was estimated to be 0·27, with a 95% credible interval of 0·14-0·44 for the first wave, whereas the posterior mean Rs decreased to 0·15 in the second and third waves. Overall, these estimates indicate that a human H7N9 pandemic is unlikely to occur in Zhejiang. The reductions in the viral transmissibility and the number of poultry-transmitted infections after the first epidemic may be attributable to the various intervention measures taken, including changes in the extent of closures of live poultry markets.
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Transmisión de Enfermedad Infecciosa , Epidemias , Subtipo H7N9 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/transmisión , Gripe Humana/virología , Número Básico de Reproducción , China/epidemiología , Humanos , Gripe Humana/epidemiología , Modelos TeóricosRESUMEN
BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Trials of magnesium treatment starting <4 days after symptom onset found no effect on poor outcome or DCI in SAH. Earlier installment of treatment might be more effective, but individual trials had not enough power for such a subanalysis. We performed an individual patient data meta-analysis to study whether magnesium is effective when given within different time frames within 24 hours after the SAH. METHODS: Patients were divided into categories according to the delay between symptom onset and start of the study medication: <6, 6 to 12, 12 to 24, and >24 hours. We calculated adjusted risk ratios with corresponding 95% confidence intervals for magnesium versus placebo treatment for poor outcome and DCI. RESULTS: We included 5 trials totaling 1981 patients; 83 patients started treatment<6 hours. For poor outcome, the adjusted risk ratios of magnesium treatment for start <6 hours were 1.44 (95% confidence interval, 0.83-2.51); for 6 to 12 hours 1.03 (0.65-1.63), for 12 to 24 hours 0.84 (0.65-1.09), and for >24 hours 1.06 (0.87-1.31), and for DCI, <6 hours 1.76 (0.68-4.58), for 6 to 12 hours 2.09 (0.99-4.39), for 12 to 24 hours 0.80 (0.56-1.16), and for >24 hours 1.08 (0.88-1.32). CONCLUSIONS: This meta-analysis suggests no beneficial effect of magnesium treatment on poor outcome or DCI when started early after SAH onset. Although the number of patients was small and a beneficial effect cannot be definitively excluded, we found no justification for a new trial with early magnesium treatment after SAH.
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Isquemia Encefálica/prevención & control , Bloqueadores de los Canales de Calcio/administración & dosificación , Aneurisma Intracraneal , Sulfato de Magnesio/administración & dosificación , Hemorragia Subaracnoidea/tratamiento farmacológico , Tiempo de Tratamiento/estadística & datos numéricos , Vasoespasmo Intracraneal/prevención & control , Aneurisma Roto/complicaciones , Bloqueadores de los Canales de Calcio/uso terapéutico , Intervención Médica Temprana , Humanos , Sulfato de Magnesio/uso terapéutico , Hemorragia Subaracnoidea/etiología , Resultado del TratamientoRESUMEN
BACKGROUND: To test the hypothesis that prognostication of treatment outcome is feasible by biomarker response at midcourse of chemoradiotherapy (CRT)/radiotherapy (RT), with respect to the plasma load of Epstein-Barr viral (EBV) DNA in nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: One hundred seven patients with stage IIB-IV NPC were prospectively studied. Plasma EBV DNA load was measured by quantitative PCR before therapy (pre-DNA), at completion of 4 weeks of CRT/RT (mid-DNA), and within 3 months of completion of therapy (post-DNA). The end points are post-DNA load, a recognized surrogate of survival, and clinical outcome. RESULTS: Ninety-three percent of patients had detectable EBV DNA before therapy (median load = 972 copies/ml). EBV DNA became undetectable in 55 (51%) patients at the end of week 4 of therapy. Detectable mid-DNA was associated with worse clinical outcome (median follow-up time, 6.2 years), for distant failure [hazard ratio (HR) 12.02, 95% confidence interval (CI) 2.78-51.93; P < 0.0001], progression-free survival (PFS; HR 4.05, 95% CI 1.89-8.67, P < 0.0001), and overall survival (OS; HR 3.29, 95% CI 1.37-7.90, P = 0.0077). Seventy-four percent of all failures were associated with detectable mid-DNA, whereas 34% of all failures were associated with detectable post-DNA. Stratification by tumor stage (IIB, III, IV) has no significant prognostic effect. CONCLUSIONS: Unfavorable EBV DNA response at midcourse of RT/CRT is an adverse prognosticator for treatment outcome, is linked to majority of all failures, and discriminates outcome better than tumor stage. The data could provide a basis for trial design that addresses alteration of therapy intensity during the latter phase of CRT, and adjuvant therapy. Validation studies are awaited.
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Biomarcadores de Tumor/sangre , ADN Viral/sangre , Infecciones por Virus de Epstein-Barr/sangre , Herpesvirus Humano 4 , Neoplasias Nasofaríngeas/virología , Carcinoma , Quimioradioterapia , Supervivencia sin Enfermedad , Infecciones por Virus de Epstein-Barr/complicaciones , Femenino , Herpesvirus Humano 4/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Tolerancia a Radiación , Reacción en Cadena en Tiempo Real de la Polimerasa , Resultado del Tratamiento , Carga ViralRESUMEN
PURPOSE: To determine the significance to patients of changes in health-related quality-of-life (HLQ) scores assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). PATIENTS AND METHODS: A subjective significance questionnaire (SSQ), which asks patients about perceived changes in physical, emotional, and social functioning and in global quality of life (global QL) and the QLQ-C30 were completed by patients who received chemotherapy for either breast cancer or small-cell lung cancer (SCLC). In the SSQ, patients rated their perception of change since the last time they completed the QLQ-C30 using a 7-category scale that ranged from "much worse" through "no change" to "much better." For each category of change in the SSQ, the corresponding differences were calculated in QLQ-C30 mean scores and effect sizes were determined. RESULTS: For patients who indicated "no change" in the SSQ, the mean change in scores in the corresponding QLQ-C30 domains was not significantly different from 0. For patients who indicated "a little" change either for better or for worse, the mean change in scores was about 5 to 10; for "moderate" change, about 10 to 20; and for "very much" change, greater than 20. Effect sizes increased in concordance with increasing changes in SSQ ratings and QLQ-C30 scores. CONCLUSION: The significance of changes in QLQ-C30 scores can be interpreted in terms of small, moderate, or large changes in quality of life as reported by patients in the SSQ. The magnitude of these changes also can be used to calculate the sample sizes required to detect a specified change in clinical trials.
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BACKGROUND: We aimed to evaluate the safety and efficacy of single-agent sunitinib in nasopharyngeal carcinoma (NPC). METHODS: Eligible patients had progressive disease after prior platinum-based chemotherapy. Sunitinib was given as continuous once-daily dosing of 37.5 mg in 4-week cycles until progression. RESULTS: Thirteen patients were enrolled. Recruitment was stopped after two patients died of hemorrhagic events. All patients had previously received curative radiotherapy (RT) to nasopharynx/neck (including nine patients who had chemoradiotherapy). Patients received a median of three cycles of sunitinib. One patient was still on sunitinib with stable disease after 24 cycles. Hemorrhagic events occurred in nine patients (64%), including epistaxis in six, hemoptyses in three and hematemesis in two patients. Prior RT to thorax was significantly associated with hemoptyses (P = 0.03). Two patients with local tumor invasion into the carotid sheath developed fatal epistaxis/hematemesis within the first cycle of sunitinib, likely due to internal carotid blowout after tumor shrinkage. CONCLUSIONS: Sunitinib demonstrated modest clinical activity in heavily pretreated NPC patients. However, the high incidence of hemorrhage from the upper aerodigestive tract in NPC patients who received prior high-dose RT to the region is of concern. Direct vascular invasion by tumors appeared to increase the risk of serious bleeding.
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Antineoplásicos/efectos adversos , Hematemesis/inducido químicamente , Hemoptisis/inducido químicamente , Indoles/efectos adversos , Neoplasias Nasofaríngeas/terapia , Pirroles/efectos adversos , Adulto , Anciano , Antineoplásicos/uso terapéutico , Carcinoma , Quimioradioterapia , Epistaxis/inducido químicamente , Femenino , Humanos , Indoles/uso terapéutico , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Pirroles/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Sunitinib , Resultado del TratamientoRESUMEN
AIMS: POU class 2 homeobox 1 (POU2F1), also known as octamer-binding transcription factor-1 (OCT-1), is a ubiquitous transcription factor that plays a key role in the regulation of genes related to inflammation and cell cycles. POU2F1 is located on chromosome 1q24, a region with linkage for Type 2 diabetes in Chinese and other populations. We examined the association of POU2F1 genetic variants with Type 2 diabetes in Hong Kong Chinese using two independent cohorts. METHODS: We genotyped five haplotype-tagging single nucleotide polymorphisms at POU2F1 in 1378 clinic-based patients with Type 2 diabetes and 601 control subjects, as well as 707 members from 179 families with diabetes. RESULTS: We found significant associations of rs4657652, rs7532692, rs10918682 and rs3767434 (OR = 1.26-1.59, 0.0003 < P(unadjusted) < 0.035) with Type 2 diabetes in the clinic-based case-control cohorts. Rs3767434 was also associated with Type 2 diabetes (OR = 1.55, P(unadjusted) = 0.013) in the family-based cohort. Meta-analysis revealed similar associations. In addition, the risk G allele of rs10918682 showed increased usage of insulin treatment during a mean follow-up period of 7 years [hazard ratio = 1.50 (1.05-2.14), P = 0.025]. CONCLUSIONS: Using separate cohorts, we observed consistent results showing the contribution of multiple variants at POU2F1 to the risk of Type 2 diabetes.
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Pueblo Asiatico/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Factor 1 de Transcripción de Unión a Octámeros/genética , Polimorfismo de Nucleótido Simple , Adulto , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Ligamiento Genético/genética , Genotipo , Hong Kong/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Factores de Riesgo , Factores de Transcripción/genéticaRESUMEN
We aimed to investigate the efficacy of an objective method using AI-based retinal characteristic analysis to automatically differentiate between two traditional Chinese syndromes that are associated with ischemic stroke. Inpatient clinical and retinal data were retrospectively retrieved from the archive of our hospital. Patients diagnosed with cerebral infarction in the department of acupuncture and moxibustion between 2014 and 2018 were examined. Of these, the patients with Qi deficiency blood stasis syndrome (QDBS) and phlegm stasis in channels (PSIC) syndrome were selected. Those without retinal photos were excluded. To measure and analyze the patients' retinal vessel characteristics, we applied a patented AI-assisted automated retinal image analysis system developed by the Chinese University of Hong Kong. The demographic, clinical, and retinal information was compared between the QDBS and PSIC patients. The t-test and chi-squared test were used to analyze continuous data and categorical data, respectively. All the selected clinical information and retinal vessel measures were used to develop different discriminative models for QDBS and PSIC using logistic regression. Discriminative efficacy and model performances were evaluated by plotting a receiver operating characteristic curve. As compared to QDBS, the PSIC patients had a lower incidence of insomnia problems (46% versus 29% respectively, p=0.023) and a higher tortuosity index (0.45 ± 0.07 versus 0.47 ± 0.07, p=0.027). Moreover, the area under the curve of the logistic model showed that its discriminative efficacy based on both retinal and clinical characteristics was 86.7%, which was better than the model that employed retinal or clinical characteristics individually. Thus, the discriminative model using AI-assisted retinal characteristic analysis showed statistically significantly better performance in QDBS and PSIC syndrome differentiation among stroke patients. Therefore, we concluded that retinal characteristics added value to the clinical differentiation between QDBS and PSIC.
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BACKGROUND: Nasopharyngeal carcinoma (NPC) is a platinum-sensitive cancer and excision repair cross-complementing group 1 (ERCC1) polymorphisms have been shown to predict survival in several cancers following platinum therapy. PATIENTS AND METHODS: This multicenter study evaluated the activity of oxaliplatin and prolonged infusion of gemcitabine ('GEMOX' regimen) in recurrent NPC. Baseline blood samples were genotyped for the presence of ERCC1-118 gene polymorphisms. RESULTS: Forty-two patients were recruited, of whom most (61%) had metastatic disease. Of the 40 patients evaluated for response, the respective overall response and disease control rates were 56.1% and 90.2%. At a median follow-up of 14.8 months, the respective median overall survival and time to progression were 19.6 months [95% confidence interval (CI) = 12.8-22 months] and 9 months (95% CI = 7.3-10 months). Grade 3-4 toxic effects were uncommon. The distribution of ERCC1-118 genotypes from 29 patients was C/C (n = 17, 40.5%), C/T (n = 10, 23.8%) and T/T (n = 2, 4.8%). No differences in survival or response rates were found between genotypes. CONCLUSIONS: GEMOX is active in the treatment of recurrent NPC. Detection of single-nucleotide gene polymorphisms from genomic DNA in peripheral blood is feasible in NPC and further studies are warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/genética , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos/genética , Endonucleasas/genética , Neoplasias Nasofaríngeas/genética , Adulto , Anciano , Carcinoma/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Compuestos Organoplatinos/uso terapéutico , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVES: This is a single center, randomized, double-blind placebo-controlled study to evaluate the NK(1)-receptor antagonist, aprepitant, in Chinese breast cancer patients. The primary objective was to compare the efficacy of aprepitant-based antiemetic regimen and standard antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients who received moderately emetogenic chemotherapy. The secondary objective was to compare the patient-reported quality of life in these two groups of patients. PATIENTS AND METHODS: Eligible breast cancer patients were chemotherapy-naive and treated with adjuvant AC chemotherapy (i.e. doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2)). Patients were randomly assigned to either an aprepitant-based regimen (day 1, aprepitant 125 mg, ondansetron 8 mg, and dexamethasone 12 mg before chemotherapy and ondansetron 8 mg 8 h later; days 2 through 3, aprepitant 80 qd) or a control arm which consisted of standard regimen (day 1, ondansetron 8 mg and dexamethasone 20 mg before chemotherapy and ondansetron 8 mg 8 h later; days 2 through 3, ondansetron 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary, patients quality of life were assessed by self-administered Functional Living Index-Emesis (FLIE). RESULTS: Of 127 patients randomized, 124 were assessable. For CINV in Cycle 1 AC, there was no significant difference in the proportion of patients with reported complete response, complete protection, total control, 'no vomiting', 'no significant nausea' and 'no nausea'. The requirement of rescue medication appears to be lesser in patients treated with the aprepitant-based regimen compared to those with the standard regimen (11% vs. 20%; P = 0.06). Assessment of FLIE revealed that while there was no difference in the nausea domain and the total score between the two groups; however, patients receiving standard antiemetic regimen had significantly worse quality of life in the vomiting domain (mean score [SD] = 23.99 [30.79]) when compared with those who received the aprepitant-based regimen (mean score [SD] = 3.40 [13.18]) (P = 0.0002). Both treatments were generally well tolerated. Patients treated with the aprepitant-based regimen had a significantly lower incidence of neutropenia (53.2% vs. 35.5%, P = 0.0468), grade >or= 3 neutropenia (21.0% vs. 45.2, P = 0.0042) and delay in subsequent cycle of chemotherapy (8.1% vs. 27.4%, P = 0.0048). CONCLUSION: The aprepitant regimen appears to reduce the requirement of rescue medication when compared with the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide, and is associated with a better quality of life during adjuvant AC chemotherapy.
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Antieméticos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Morfolinas/administración & dosificación , Náusea/tratamiento farmacológico , Ondansetrón/administración & dosificación , Vómitos/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Aprepitant , Carcinoma Ductal de Mama/tratamiento farmacológico , China , Dexametasona/administración & dosificación , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Náusea/inducido químicamente , Calidad de Vida , Vómitos/inducido químicamenteAsunto(s)
Pueblo Asiatico/genética , Carcinoma Hepatocelular/genética , Portador Sano/virología , Antígenos HLA/genética , Virus de la Hepatitis B/genética , Neoplasias Hepáticas/genética , Alelos , Antígenos Virales/sangre , Carcinoma Hepatocelular/virología , Estudios de Casos y Controles , Hepatitis B/complicaciones , Virus de la Hepatitis B/inmunología , Hong Kong , Humanos , Neoplasias Hepáticas/virología , Polimorfismo Genético , Medición de Riesgo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
BACKGROUND: The toxicity of a given cancer therapy is an important end point in clinical trials examining the potential costs and benefits of that therapy. Treatment-related toxicity is conventionally measured with one of several toxicity criteria grading scales, even though the reliability and validity of these scales have not been established. PURPOSE: We determined the reliability of the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) expanded toxicity scale and the World Health Organization (WHO) standard toxicity scale by use of a clinical simulation of actual patients. METHODS: Seven experienced data managers each interviewed 12 simulated patients and scored their respective acute toxic effects. Inter-rater agreement (agreement between multiple raters of the same case) was calculated using the kappa (kappa) statistic across all seven randomly assigned raters for each of 18 toxicity categories (13 NCIC-CTG and five WHO categories). Intra-rater agreement (agreement within the same rater on one case rated on separate occasions) was calculated using kappa over repeated cases (where raters were blinded to the repeated nature of the subjects). Proportions of agreement (estimate of the probability of two randomly selected raters assigning the same toxicity grade to a given case) were also calculated for inter-rater agreement. Since minor lack of agreement might have adversely affected these statistics of agreement, both kappa and proportion of agreement analyses were repeated for the following condensed grading categories: none (0) versus low-grade (1 or 2) versus high-grade (3 or 4) toxicity present. RESULTS: Modest levels of inter-rater reliability were demonstrated in this study with kappa values that ranged from 0.50 to 1.00 in laboratory-based categories and from -0.04 to 0.82 for clinically based categories. Proportions of agreement for clinical categories ranged from 0.52 to 0.98. Condensing the toxicity grades improved statistics of agreement, but substantial lack of agreement remained (kappa range, -0.04-0.82; proportions of agreement range, 0.67-0.98). CONCLUSIONS: Experienced data managers, when interviewing patients, draw varying conclusions regarding toxic effects experienced by such patients. Neither the NCIC-CTG expanded toxicity scale nor the WHO standard toxicity scale demonstrated a clear superiority in reliability, although the breadth of toxic effects recorded differed.
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Terapia Combinada/efectos adversos , Recolección de Datos/métodos , Canadá , Ensayos Clínicos como Asunto/métodos , Humanos , Neoplasias/terapia , Variaciones Dependientes del Observador , Distribución Aleatoria , Reproducibilidad de los Resultados , Organización Mundial de la SaludRESUMEN
In four phase II trials of trimetrexate given iv daily for 5 days, we noted marked variability among patients in the development of severe or life-threatening toxic effects. In an effort to define which of 15 patient characteristics were associated with toxic effects of this degree, we have carried out single-factor and multifactor analyses on toxic effects during the first cycle of therapy in 68 patients. The final logistic regression model identified both low pretreatment serum protein levels and metastatic liver disease as significant correlates of severe toxic effects (P = .02 and P = .0005, respectively). While drug dose was an important element of the best logistic model, its statistical significance was only borderline. Trimetrexate is extensively protein bound and is cleared primarily by hepatic metabolism, so it is not unreasonable to believe that alteration in protein binding of the drug or in metabolic capacity of the liver could produce enhanced toxic effects. Although the validity of these predictors should be confirmed, it seems prudent to recommend lower starting doses of trimetrexate for patients with metastatic liver disease and/or low protein levels and dose escalation if toxic effects allow it.
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Antineoplásicos/efectos adversos , Antagonistas del Ácido Fólico/efectos adversos , Quinazolinas/efectos adversos , Antineoplásicos/metabolismo , Proteínas Sanguíneas/análisis , Evaluación de Medicamentos , Femenino , Antagonistas del Ácido Fólico/metabolismo , Humanos , Neoplasias Hepáticas/secundario , Masculino , Unión Proteica , Quinazolinas/metabolismo , TrimetrexatoRESUMEN
BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Alopecia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Terapia Combinada , Estudios Cruzados , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Náusea/inducido químicamente , Estadificación de Neoplasias , Neutropenia/inducido químicamente , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/cirugía , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Análisis de Supervivencia , Trombocitopenia/inducido químicamente , Factores de Tiempo , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
We performed a phase I trial of CI-937 (DUP937), an anthrapyrazole, with the following objectives: (a) to determine the maximally tolerated dose in humans; (b) to define the toxicity spectrum of this agent; (c) to describe the pharmacokinetics of the drug; (d) to test a pharmacokinetics based hypothesis of dose escalation; and (e) to relate drug pharmacokinetics to pharmacodynamics. CI-937 was administered as a single bolus injection every 3-4 weeks at doses ranging from 3.6 to 25.2 mg/m2. Thirty-two patients and 57 courses were evaluable for toxicity. Pharmacokinetic analysis was performed in 30 patients on the first course using a sensitive and selective radioimmunoassay. The maximally tolerated dose in patients with no prior therapy was 25.2 mg/m2 and dose-limiting toxicity was neutropenia. Thrombocytopenia, nausea, vomiting, stomatitis, and alopecia were mild. A partial response was recorded in a patient with mesothelioma. The area under the curve increased linearly with dose, and total body clearance of CI-937 was independent of dose. The mean total body clearance was 107 +/- 55.8 ml/min/m2, mean steady state volume of distribution was 492 +/- 469 liters/m2, and terminal half-life was 3.78 +/- 2.86 days. The extended factors of 2 methods of pharmacologically guided dose escalation were intended for use but ultimately were equivalent to that of the modified Fibonacci dose escalation method. Dose and the area under the curve were significant predictors of a percentage change in WBC and neutrophil count in a univariate analysis. Only dose and baseline neutrophil count predicted a percentage change in WBCs in a multifactor analysis. Dose and prior chemotherapy predicted percentage change in neutrophil count in a multifactor analysis. We conclude that the dose-limiting toxicity of CI-937 is neutropenia and that the recommended phase II starting dose is 22 mg/m2.
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Antraquinonas/farmacocinética , Antineoplásicos/farmacocinética , Pirazoles/farmacocinética , Adulto , Anciano , Agranulocitosis/inducido químicamente , Antraquinonas/administración & dosificación , Antraquinonas/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Evaluación de Medicamentos , Femenino , Humanos , Recuento de Leucocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/metabolismo , Neutropenia/inducido químicamente , Pirazoles/administración & dosificación , Pirazoles/efectos adversosRESUMEN
PURPOSE: Because one of the goals of chemotherapy for metastatic breast cancer is to provide symptom palliation, we were interested in identifying the relationship between tumor shrinkage and improvement in disease-related symptoms. PATIENTS AND METHODS: Three hundred patients enrolled onto a randomized trial of metastatic breast cancer formed the basis of our study. The nine most common baseline symptoms were identified and followed. Changes from baseline (improvement, stable, worsening) were defined using patient responses to a quality-of-life (QoL) questionnaire (the European Organization for Research and Treatment of Cancer EORTC QLQ-C30) as well as using graded toxicity data collected on case report forms (CRFs). The association between symptom improvement and tumor response was assessed using a linear trend test via a logistic regression model. RESULTS: The most commonly reported baseline symptoms were cancer pain in 38% (CRF data) and 81% of patients (QoL data) and tiredness in 26% (CRF data) and 89% (QoL data) of patients. Three symptoms-cancer pain, shortness of breath, and abnormal mood-showed a significant relationship between improvement and objective response, using both CRF and QoL assessments. Constipation, anorexia, and nausea showed a similar trend when QoL data were used but not when CRF information was used. The converse was seen for lethargy. There was no correlation between symptom change and response for cough and insomnia. CONCLUSION: For some symptoms, we found a significant association between symptom improvement and objective tumor regression. In these cases, symptom improvement was greatest in those patients who had complete or partial responses, followed by those with stable disease and then those with progressive disease. Further work in this area will be useful in determining the surrogate value of objective tumor response in identifying the efficacy of palliative chemotherapy.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/psicología , Cuidados Paliativos , Calidad de Vida , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tos/etiología , Tos/terapia , Disnea/etiología , Disnea/terapia , Femenino , Humanos , Trastornos del Humor/etiología , Trastornos del Humor/terapia , Dolor/etiología , Manejo del Dolor , Resultado del TratamientoRESUMEN
PURPOSE: To determine the significance to patients of changes in health-related quality-of-life (HLQ) scores assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). PATIENTS AND METHODS: A subjective significance questionnaire (SSQ), which asks patients about perceived changes in physical, emotional, and social functioning and in global quality of life (global QL) and the QLQ-C30 were completed by patients who received chemotherapy for either breast cancer or small-cell lung cancer (SCLC). In the SSQ, patients rated their perception of change since the last time they completed the QLQ-C30 using a 7-category scale that ranged from "much worse" through "no change" to "much better." For each category of change in the SSQ, the corresponding differences were calculated in QLQ-C30 mean scores and effect sizes were determined. RESULTS: For patients who indicated "no change" in the SSQ, the mean change in scores in the corresponding QLQ-C30 domains was not significantly different from 0. For patients who indicated "a little" change either for better or for worse, the mean change in scores was about 5 to 10; for "moderate" change, about 10 to 20; and for "very much" change, greater than 20. Effect sizes increased in concordance with increasing changes in SSQ ratings and QLQ-C30 scores. CONCLUSION: The significance of changes in QLQ-C30 scores can be interpreted in terms of small, moderate, or large changes in quality of life as reported by patients in the SSQ. The magnitude of these changes also can be used to calculate the sample sizes required to detect a specified change in clinical trials.