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BACKGROUND: Caring for a child with a neurodisability (ND) impacts the financial decisions, relationships and well-being of family members, but evidence on the economic trajectories of families throughout the life course is missing. METHODS: Using data from the Panel Study of Income Dynamics, we tracked the families of 3317 children starting 5 years before childbirth until the child reached 20 years of age. We used regression and latent growth curve modelling to estimate trajectories of poverty and economic hardship over time. RESULTS: Families with a child with an ND had higher rates of poverty and economic hardship prior to childbirth and persistently over time. Analysis uncovered five latent trajectories for each indicator. After controlling for family and caregiver characteristics that preceded the birth of the child, raising a child with an ND was not associated with a unique trajectory of poverty. Families raising a child with an ND were however more likely to experience persistent economic hardship. CONCLUSIONS: The study establishes descriptive evidence for how having a child with an ND relates to changes in family economic conditions. The social and economic conditions that precede the child's birth seem to be driving the economic inequalities observed later throughout the life course.
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Niños con Discapacidad/estadística & datos numéricos , Epilepsia/epidemiología , Familia , Trastornos del Neurodesarrollo/epidemiología , Pobreza/estadística & datos numéricos , Adolescente , Adulto , Niño , Preescolar , Epilepsia/economía , Femenino , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Trastornos del Neurodesarrollo/economía , Pobreza/economía , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: The application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment. PATIENTS AND METHODS: We used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy. RESULTS: Despite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole-exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel. CONCLUSION: We show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available.
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Ácidos Nucleicos Libres de Células/genética , Melanoma/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-kit/genética , Neoplasias Vaginales/tratamiento farmacológico , Adulto , Anciano , Biomarcadores Farmacológicos , Carboplatino/administración & dosificación , Ácidos Nucleicos Libres de Células/efectos de los fármacos , ADN de Neoplasias/efectos de los fármacos , ADN de Neoplasias/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mesilato de Imatinib/administración & dosificación , Melanoma/genética , Melanoma/patología , Persona de Mediana Edad , Mutación , Paclitaxel/administración & dosificación , Medicina de Precisión , Neoplasias Vaginales/genética , Neoplasias Vaginales/patología , Secuenciación del ExomaRESUMEN
BACKGROUND: Over the past decade, numerous reports describe the generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling and preclinical drug testing, the requirement of a tissue biopsy limits the available patient population, particularly those with advanced oligometastatic disease. Conversely, 'liquid biopsies' such as circulating tumour cells (CTCs) are minimally invasive and easier to obtain. Here, we present a clinical case study of a NSCLC patient with advanced metastatic disease, a never smoker whose primary tumour was EGFR and ALK wild-type. We demonstrate for the first time, tumorigenicity of their CTCs to generate a patient CTC-derived eXplant (CDX). PATIENTS AND METHODS: CTCs were enriched at diagnosis and again 2 months later during disease progression from 10 ml blood from a 48-year-old NSCLC patient and implanted into immunocompromised mice. Resultant tumours were morphologically, immunohistochemically, and genetically compared with the donor patient's diagnostic specimen. Mice were treated with cisplatin and pemetrexed to assess preclinical efficacy of the chemotherapy regimen given to the donor patient. RESULTS: The NSCLC CDX expressed lung lineage markers TTF1 and CK7 and was unresponsive to cisplatin and pemetrexed. Examination of blood samples matched to that used for CDX generation revealed absence of CTCs using the CellSearch EpCAM-dependent platform, whereas size-based CTC enrichment revealed abundant heterogeneous CTCs of which â¼80% were mesenchymal marker vimentin positive. Molecular analysis of the CDX, mesenchymal and epithelial CTCs revealed a common somatic mutation confirming tumour origin and showed CDX RNA and protein profiles consistent with the predominantly mesenchymal phenotype. CONCLUSIONS: This study shows that the absence of NSCLC CTCs detected by CellSearch (EpCAM(+)) does not preclude CDX generation, highlighting epithelial to mesenchymal transition and the functional importance of mesenchymal CTCs in dissemination of this disease.
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Biomarcadores de Tumor/genética , Carcinogénesis/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Células Neoplásicas Circulantes/patología , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Proteínas de Unión al ADN/genética , Transición Epitelial-Mesenquimal/genética , Humanos , Células Madre Mesenquimatosas/patología , Ratones , Mutación , Células Neoplásicas Circulantes/efectos de los fármacos , Células Madre Neoplásicas/patología , Pemetrexed/administración & dosificación , Factores de Transcripción/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: To determine if using a combination of hospital administrative data and ambulatory care physician billings can accurately identify patients with congestive heart failure (CHF), we tested 9 algorithms for identifying individuals with CHF from administrative data. METHODS: The validation cohort against which the 9 algorithms were tested combined data from a random sample of adult patients from EMRALD, an electronic medical record database of primary care physicians in Ontario, Canada, and data collected in 2004/05 from a random sample of primary care patients for a study of hypertension. Algorithms were evaluated on sensitivity, specificity, positive predictive value, area under the curve on the ROC graph and the combination of likelihood ratio positive and negative. RESULTS: We found that that one hospital record or one physician billing followed by a second record from either source within one year had the best result, with a sensitivity of 84.8% and a specificity of 97.0%. CONCLUSION: Population prevalence of CHF can be accurately measured using combined administrative data from hospitalization and ambulatory care.
TITLE: Repérage des cas d'insuffisance cardiaque congestive à partir de données administratives : étude de validation utilisant des dossiers de patients en soins primaires. INTRODUCTION: En vue de déterminer si l'utilisation conjuguée des données administratives hospitalières et des factures présentées par les médecins au titre des soins ambulatoires pouvait permettre de repérer avec exactitude les patients souffrant d'insuffisance cardiaque congestive (ICC), nous avons mis à l'essai neuf algorithmes pour repérer à partir de données administratives les personnes souffrant d'ICC. MÉTHODOLOGIE: La cohorte de validation par rapport à laquelle les essais ont été effectués combinait des données provenant d'un échantillon aléatoire de patients adultes inscrits dans la base de données EMRALD de dossiers médicaux électroniques des médecins de premier recours en Ontario, au Canada, et des données recueillies en 2004-2005 à partir d'un échantillon aléatoire de patients en soins primaires pour une étude sur l'hypertension. On a évalué la sensibilité, la spécificité, la valeur prédictive positive, l'aire sous la courbe ROC et la combinaison des rapports de vraisemblance positif et négatif des algorithmes. RÉSULTATS: Nous avons constaté qu'un dossier d'hospitalisation ou de facturation de médecin suivi d'un second dossier provenant de l'une ou l'autre de ces sources dans la même année produisait les meilleurs résultats, avec une sensibilité de 84,8 % et une spécificité de 97,0 %. CONCLUSION: Nous concluons que la prévalence de l'ICC dans la population peut être mesurée avec exactitude à partir de données administratives issues de l'hospitalisation et des soins ambulatoires.
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Algoritmos , Minería de Datos/métodos , Registros Electrónicos de Salud , Insuficiencia Cardíaca/epidemiología , Atención Primaria de Salud , Femenino , Humanos , Masculino , Ontario/epidemiología , Prevalencia , Sensibilidad y EspecificidadRESUMEN
T cells bearing chimeric antigen receptors (CARs) are broadly categorised into first- and second-generation receptors. Second-generation CARs contain a co-stimulatory signalling molecule and have been shown to secrete IL-2, undergo greater proliferation and to have enhanced persistence in vivo. However, we have shown that T cells bearing a first-generation CAR containing a CD19-targeting scFv (single-chain variable fragment) and the CD3ζ-signalling domain are able to produce IL-2 upon co-culture with CD19(+) B-cell lymphomas independent of CD28 activity. Here, we report that signalling through endogenous CD2 following ligation with its ligands, CD48 in mouse and CD58 in humans, drives IL-2 production by first-generation CD19-specific CAR. Moreover, the high levels of IL-2 produced by human T cells engrafted with a second-generation CD28-containing CAR during target-cell recognition are dependent to a degree upon CD2 receptor activity. These observations highlight the fact that the functional activity induced by T-cell-expressed CARs is dependent upon endogenous 'natural' receptor interactions. A deeper understanding of the role of these activities will serve to further refine the design of future CARs to either exploit or avoid these interactions.
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Antígenos CD2/metabolismo , Interleucina-2/biosíntesis , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígenos CD2/inmunología , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , Antígeno CD48 , Antígenos CD58/inmunología , Antígenos CD58/metabolismo , Línea Celular , Humanos , Ligandos , Ratones , Unión Proteica , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
PURPOSE: This study was designed to determine whether changes in length of stay and 30-day readmission, reoperation, and excision rates for the ileal pouch-anal anastomosis occurred over time and with changes in surgical technique and hospital volume. METHODS: Using three population-based administrative databases, data on all ileal pouch-anal anastomoses performed in the province of Ontario between January 1992 and June 1998 were obtained. The effect of age, gender, stage of the procedure, year of surgery, and hospital volume were examined for their effect on length of stay and readmission, reoperation, and excision rates. RESULTS: There were 1,285 ileal pouch-anal anastomoses performed in 58 hospitals. There was a significant decrease in length of stay and reoperation and excision rates but a concommitant increase in readmission rate during the study period. Patients younger than aged 40 years had a significantly lower length of stay and excision rate. Patients who had a two-stage procedure had a shorter length of stay, readmission, and reoperative rate compared with those having a three-stage procedure. Hospital volume was a significant predictor of need for reoperation and excision with both low-volume and medium-volume hospitals having significantly higher rates than high-volume hospitals. CONCLUSIONS: Outcome after ileal pouch-anal anastomosis has improved. It is significantly better in patients younger than aged 40 years, having a two-stage procedure, and where surgery is performed at high-volume hospitals. It is likely that both modifications in surgical technique and surgical experience have led to improvements in clinical outcome after ileal pouch-anal anastomosis.
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Anastomosis Quirúrgica/efectos adversos , Reservorios Cólicos/efectos adversos , Proctocolectomía Restauradora/efectos adversos , Adulto , Factores de Edad , Canal Anal/cirugía , Anastomosis Quirúrgica/métodos , Anastomosis Quirúrgica/estadística & datos numéricos , Estudios de Cohortes , Reservorios Cólicos/estadística & datos numéricos , Bases de Datos como Asunto , Femenino , Humanos , Tiempo de Internación , Masculino , Ontario , Proctocolectomía Restauradora/métodos , Proctocolectomía Restauradora/estadística & datos numéricos , Análisis de Regresión , Reoperación/estadística & datos numéricos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
AIM: To examine changes in radiotherapy (RT) use, cause-specific survival (CSS), and overall survival (OS) in a population-based cohort of Hodgkin's disease (HD) patients diagnosed from 1982 to 1996. MATERIALS AND METHODS: Adult patients with HD diagnosed from 1 January 1982 to 31 December 1996 (n = 3957) were identified from the Ontario Cancer Registry. The cohort was divided into three consecutive 5-year periods: 1982-1986, 1987-1991, and 1992-1996. RT use, CSS and OS in each of these three periods were compared. For the entire cohort, the cumulative incidence of different causes of death was calculated. RESULTS: The proportion of patients receiving RT within 11 weeks of diagnosis declined over the three consecutive periods (25.1%, 15.6%, 11.7%, P < 0.001), as did the proportion receiving RT within 45 weeks (57.0%, 51.0%, 48.1%; P < 0.001). There was a significant increase in 5-year CSS over time (81%, 87%, 89%; P < 0.001), and OS (72%, 77%, 82%; P < 0.001), which remained significant in multivariable analyses. The cumulative incidence of death from causes other than HD was equal to the incidence of HD-related death within 12 years of diagnosis. CONCLUSIONS: There was a significant decline in the use of RT as the primary treatment modality and as part of the initial management of HD from 1982-1996 in Ontario. A greater proportion of patients received their RT after a delay consistent with the receipt of prior chemotherapy. There was also a significant increase in the CSS and OS over this period. These findings are in keeping with the adoption of effective chemotherapy in the treatment of HD.
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Enfermedad de Hodgkin/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Causas de Muerte , Estudios de Cohortes , Femenino , Enfermedad de Hodgkin/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: The combination of T, N, and M classifications into stage groupings was designed to facilitate a number of activities including: the estimation of prognosis and the comparison of therapeutic interventions among similar groups of cases. The authors tested the UICC/AJCC 5th edition stage grouping and seven other TNM-based groupings proposed for head and neck cancer to determine their ability to meet these expectations in a specific site: carcinoma of the tonsillar region. METHODS: The authors defined four criteria to assess each stage grouping scheme: 1) The subgroups defined by T and N comprising a given group within a grouping scheme have similar survival rates (hazard consistency); 2) The survival rates differ across the groups (hazard discrimination); 3) The prediction of cure is high (outcome prediction); and 4) The distribution of patients among the groups is balanced. The authors identified or derived a measure for each criterion and the findings were summarized using a scoring system. The range of scores was from 0 (best) to 7 (worst). Data were from a retrospective chart review on 642 cases of carcinoma of the tonsillar region treated with radiotherapy for cure at the Princess Margaret Hospital from 1970-1991. None of the patients had distant metastases. RESULTS: The scheme proposed by Synderman and Wagner, which was published in Otolaryngology Head and Neck Surgery in 1995 (vol.112, pages 691-4), scored best at 1.2. The UICC/AJCC scheme scored worst at 6.1. The hazard consistency ranged from a 3.1% average survival difference to 6.7% across the 8 schemes. The hazard discrimination measure varied by 28% from the best to worst scheme. Prediction varied by up to almost twofold across the schemes assessed. The distribution of patients varied from expected by between 0.13% and 0.57%. CONCLUSION: UICC/AJCC stage groupings were defined without empirical investigation. When tested, this scheme did not perform as well as any of seven empirically-derived schemes the authors evaluated. The results of the current study suggest that the usefulness of the TNM system can be enhanced by optimizing the design of stage groupings through empirical investigation.
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Carcinoma de Células Escamosas/clasificación , Neoplasias de Cabeza y Cuello/clasificación , Neoplasias Tonsilares/clasificación , Neoplasias Tonsilares/patología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Humanos , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Neoplasias Tonsilares/mortalidadRESUMEN
BACKGROUND AND PURPOSE: Several reports have linked chiropractic manipulation of the neck to dissection or occlusion of the vertebral artery. However, previous studies linking such strokes to neck manipulation consist primarily of uncontrolled case series. We designed a population-based nested case-control study to test the association. METHODS: Hospitalization records were used to identify vertebrobasilar accidents (VBAs) in Ontario, Canada, during 1993-1998. Each of 582 cases was age and sex matched to 4 controls from the Ontario population with no history of stroke at the event date. Public health insurance billing records were used to document use of chiropractic services before the event date. RESULTS: Results for those aged <45 years showed VBA cases to be 5 times more likely than controls to have visited a chiropractor within 1 week of the VBA (95% CI from bootstrapping, 1.32 to 43.87). Additionally, in the younger age group, cases were 5 times as likely to have had >/=3 visits with a cervical diagnosis in the month before the case's VBA date (95% CI from bootstrapping, 1.34 to 18.57). No significant associations were found for those aged >/=45 years. CONCLUSIONS: While our analysis is consistent with a positive association in young adults, potential sources of bias are also discussed. The rarity of VBAs makes this association difficult to study despite high volumes of chiropractic treatment. Because of the popularity of spinal manipulation, high-quality research on both its risks and benefits is recommended.
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Manipulación Espinal , Accidente Cerebrovascular/epidemiología , Disección de la Arteria Vertebral/epidemiología , Insuficiencia Vertebrobasilar/epidemiología , Adulto , Estudios de Casos y Controles , Causalidad , Comorbilidad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Ontario/epidemiologíaRESUMEN
Activating point mutations in codons 12, 13, or 61 of the K-ras and N-ras genes have been reported to occur in up to 40% of patients with multiple myeloma at presentation. In a study of 34 presentation myeloma cases using a sensitive polymerase chain reaction-restriction fragment length polymorphism strategy on enriched tumor cell populations, the present study detected N-ras codon 61 mutation-positive cells in all patients. Quantitative plaque hybridization using allele-specific oligonucleotide probes showed that in the majority of patients, ras mutation-positive cells comprise only a subpopulation of the total malignant plasma cell compartment (range, 12%-100%). Using clonospecific point mutations in the 5' untranslated region of the BCL6 gene to quantitate clonal B cells in FACS-sorted bone marrow populations from 2 patients, the representation of ras mutation-positive cells was independent of immunophenotype. These observations imply that mutational activation of N-ras codon 61 is a mandatory event in the pathogenesis of multiple myeloma; such mutations provide a marker of intraclonal heterogeneity that may originate at an earlier ontologic stage than immunophenotypic diversification of the malignant B cell clone.
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Codón/genética , ADN de Neoplasias/genética , Genes ras , Mieloma Múltiple/genética , Mutación , Regiones no Traducidas 5'/genética , Sustitución de Aminoácidos , Separación Celular , Transformación Celular Neoplásica/genética , Células Clonales/química , Células Clonales/patología , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Masculino , Mieloma Múltiple/patología , Mutación Missense , Células Madre Neoplásicas/química , Células Madre Neoplásicas/patología , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Factores de Transcripción/genéticaRESUMEN
OBJECTIVE: To provide a population-based description of current practice in the use of hormonal management of prostate cancer. DESIGN,SETTING & PARTICIPANTS: All men in Ontario, Canada, age 65 and older, with confirmed prostate cancer starting maintained hormonal therapy, from July 1992 through December 1998 (11,435 patients). Data sources included the provincial drug benefit plan, hospital services data, and Ontario Cancer Registry. OUTCOME MEASURES: Rates and trends in the use of: surgical or medical castration; total androgen blockade (TAB); and monotherapies based on steroidal or nonsteroidal antiandrogens. RESULTS: In 5.5 years, use of 'standard' therapy based on surgical or medical castration alone dropped from 36% to 26% of patients, while the use of TAB doubled from 22% to 41%. Approximately 15% of patients received nonsteroidal antiandrogens without evidence of therapy aimed at central androgen blockade. Marked regional differences were observed and not explained by patient age or practitioner specialty. CONCLUSIONS: New hormonal therapies for prostate cancer have implications in terms of disease control, patient survival, side effects, and costs. Rapid growth in prescribing of antiandrogens may represent an unnecessary expense for public or private payers, and observed regional differences likely reflect lack of consensus on the relative merit of TAB. Patients and practitioners must have current information on the advantages and disadvantages of different therapeutic options, and quality-of life, particularly with respect to emerging drug therapies.
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Antineoplásicos Hormonales/uso terapéutico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Humanos , Modelos Logísticos , Masculino , OntarioRESUMEN
We compared the management and outcome of glottic cancer in Ontario, Canada to that in the Surveillance, Epidemiology and End Results (SEER) Program areas in the United States to determine whether the greater use of primary radiotherapy with surgery reserved for salvage in Ontario was associated with similar survival and better larynx retention rates than the U.S. approach where primary surgery is used more often. Electronic, clinical and hospital data were linked to cancer registry data and supplemented by chart review where necessary. Initial treatment and survival in patients diagnosed in the SEER areas from 1988 through 1994 were compared to patients from Ontario diagnosed from 1982 through 1995. Actuarial laryngectomy rates were compared for patients over 65 at diagnosis in the two regions. Analyses were conducted over all cases and stratified by disease stage. In localized disease (T1 or T2), conservative treatment was the most common initial treatment in both regions, although total laryngectomy was used more often in SEER than Ontario (6.2% vs. 0.2%, respectively, P <.001). In advanced disease (T3 or T4), total laryngectomy was more commonly used as initial treatment in SEER (62.9% vs. 21.0% in Ontario, P < or =.001). Over all cases, the relative survival rate was 80% in Ontario at 5 years compared to 78% in SEER (P =.33). In localized disease, the relative survival rates were 4 to 5% higher in Ontario from the second year on, while in advanced disease 2 to 3% higher rates in SEER did not approach statistical significance. Actuarial laryngectomy rates at 3 years differed between the two regions, with a 4% higher rate in SEER (P =.01). In localized disease, 12.6% of Ontario patients had a laryngectomy by 3 years postdiagnosis compared to 17.9% in SEER (P =.05). In advanced disease, the rates were 63.3% and 79.2%, respectively (P =.07). There are large differences in the management of glottic cancer between the SEER areas of the U.S. and Ontario and no evidence that a policy emphasizing radiotherapy with surgery reserved for salvage is associated with worse survival. Ultimate laryngectomy rates are lower in Ontario for localized disease and may be lower for advanced disease. Conservation treatment should be used for localized disease while the treatment decision in advanced disease may be especially sensitive to patient values for voice retention versus initial cure.
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Glotis , Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/cirugía , Anciano , Sesgo , Canadá/epidemiología , Estudios de Cohortes , Terapia Combinada , Femenino , Humanos , Neoplasias Laríngeas/mortalidad , Laringectomía/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pautas de la Práctica en Medicina , Sistema de Registros , Programa de VERF , Tasa de Supervivencia , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: To identify patterns and predictors of relapse and to determine whether the time to relapse influences survival. STUDY DESIGN: Multivariate anal. ysis of prospective database. METHODS: We present findings in 446 consecutive prospective patients from a regional cancer center with invasive squamous cell carcinoma who were treated for cure and were declared disease free. Time to relapse, site of relapse, and survival are reported by stage and site using bivariate and multivariate analysis. RESULTS: Thirty-six percent of patients relapsed. The median time to relapse was 8.3 months, and 95% of relapses occurred within 3 years. T stage in the TNM staging system was associated with relapse, and N stage was not. In patients who relapsed before the median time to relapse, prognosis was worse than in those who relapsed after that time.
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Carcinoma de Células Escamosas/mortalidad , Neoplasias de Cabeza y Cuello/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Adulto , Anciano , Carcinoma de Células Escamosas/patología , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Análisis de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: Prior comparisons of administrative versus clinical data for creating coronary artery bypass graft (CABG) surgery outcome "report cards" are all from the United States and yield inconsistent conclusions regarding the validity of administrative data report cards. In this study, we compared 2 CABG surgery outcome report cards for Ontario, Canada: one derived from clinical data from the Cardiac Care Network of Ontario and one derived from administrative data from the Canadian Institute for Health Information. METHODS: Data from 4 fiscal years, 1992-93 through 1995-96, were used. The Canadian Institute for Health Information report card was derived from administrative data only. The Cardiac Care Network report card drew on prospectively collected clinical information that included variables such as left ventricular ejection fraction but also required linkages to the Canadian Institute for Health Information data for ascertainment of selected comorbidities and in-hospital mortality rates. Logistic regression models were used to calculate risk-adjusted death rates for each of the 9 hospitals performing CABG surgery in Ontario. RESULTS: The risk-adjusted death rates were quite similar between data sources for 7 of the 9 hospitals. For 2 hospitals, rather large absolute differences in adjusted death rates of 0.58% and 0.64% were seen between report cards. There was a strong correlation between data sources for risk-adjusted hospital death rates (intraclass correlation coefficient = 0.927, P <.001) and for rankings of adjusted hospital death rates (Spearman correlation coefficient = 0.828, P =.02). CONCLUSION: These results from Ontario, Canada, reveal general similarities between administrative and clinical data report cards for CABG surgery. However, clinical data are likely needed if individual hospitals are to be publicly scrutinized in outcome report cards.
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Puente de Arteria Coronaria/normas , Servicios de Información , Auditoría Médica , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Adulto , Anciano , Canadá , Puente de Arteria Coronaria/efectos adversos , Mortalidad Hospitalaria , Hospitales/normas , Humanos , Persona de Mediana Edad , Complicaciones Posoperatorias , Medición de RiesgoRESUMEN
HAP1, also known as APE/Ref-1, is the major apurinic/apyrimidinic (AP) endonuclease in human cells. Previous structural studies have suggested a possible role for the Asp-210 residue of HAP1 in the enzymatic function of this enzyme. Here, we demonstrate that substitution of Asp-210 by Asn or Ala eliminates the AP endonuclease activity of HAP1, while substitution by Glu reduces specific activity approximately 500-fold. Nevertheless, these mutant proteins still bind efficiently to oligonucleotides containing either AP sites or the chemically unrelated bulky p-benzoquinone (pBQ) derivatives of dC, dA and dG, all of which are substrates for HAP1. These results indicate that Asp-210 is required for catalysis, but not substrate recognition, consistent with enzyme kinetic data indicating that the HAP1-D210E protein has a 3000-fold reduced K(cat )for AP site cleavage, but an unchanged K(m). Through analysis of the binding of Asp-210 substitution mutants to oligonucleotides containing either an AP site or a pBQ adduct, we conclude that the absence of Asp-210 allows the formation of a stable HAP1-substrate complex that exists only transiently during the catalytic cycle of wild-type HAP1 protein. We interpret these data in the context of the structure of the HAP1 active site and the recently determined co-crystal structure of HAP1 bound to DNA substrates.
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Liasas de Carbono-Oxígeno/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa , Benzoquinonas/metabolismo , Sitios de Unión , Liasas de Carbono-Oxígeno/química , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Escherichia coli , Humanos , Enlace de Hidrógeno , Cinética , Modelos Moleculares , Mutación , Oligodesoxirribonucleótidos/metabolismo , Estructura Secundaria de Proteína , Especificidad por SustratoRESUMEN
BACKGROUND: In North America, cigarette smoking and/or alcohol consumption not only cause head and neck cancer, they also cause many of the other diseases, illnesses, and conditions, also known as comorbidities, frequently found in our patients. Comorbidities can influence treatment decision making and treatment outcome. The aim of this study is to quantify the increased risk of comorbidity in our patients. METHOD: The survival of 655 consecutive patients with squamous cell carcinoma from a regional cancer center is analyzed. We compare the survival curves for all-cause death, death from cancer, and death from noncancer causes to the expected survival of age/sex-matched populations of Ontario residents, Canadian smokers, and Canadian nonsmokers. RESULTS: Of those patients who had not survived 5 years, 59% died of their index tumor, 23% would have been expected to die if they did not have head and neck cancer, and 18% died of the increased comorbidity associated with being a patient with head and neck cancer. DISCUSSION: Comorbidity, and specifically the increased comorbidity found in patients with head and neck cancer, is an important factor in overall survival.
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Carcinoma de Células Escamosas/epidemiología , Causas de Muerte , Neoplasias de Cabeza y Cuello/epidemiología , Análisis Actuarial , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Comorbilidad , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Morbilidad/tendencias , Ontario/epidemiología , Sistema de Registros , Factores de Riesgo , Distribución por Sexo , Fumar/epidemiología , Análisis de SupervivenciaRESUMEN
OBJECTIVE: We compared treatment practice and outcome in glottic cancer in Ontario, Canada to that in the Surveillance, Epidemiology and End Results (SEER) program areas in the United States to determine whether the Ontario emphasis on the use of delayed combined therapy was associated with similar survival and better laryngectomy-free survival than the U.S. approach, which emphasizes greater use of surgery. METHODS: Electronic, clinical, and hospital data were linked to cancer registry data. The study groups compared on survival comprised all patients diagnosed from 1982 to the end of 1991 in Ontario (2324 patients) and in the SEER areas (5715 patients). Comparisons on initial treatment, laryngectomy rates, and laryngectomy-free survival were limited to subsets of these study populations due to data availability. Initial treatment data were provided by the SEER registries in the U.S. and by the cancer clinic and hospitalization data in Ontario. Information about laryngectomies performed subsequent to initial treatment was available from Medicare hospitalization data in the U.S. and from Canadian Institute for Health Information hospitalization data in Ontario. RESULTS: Although radiotherapy was the most common initial treatment in both areas, it was used more often in Ontario (84.4% versus 63.2% in the U.S. [p < 0.001]). Relative survival was not statistically different with a relative risk comparing SEER to Ontario of 1.09, 95% confidence interval (CI) (0.93, 1.29). Laryngectomy rates were similar with a relative risk of 1.01, 95% CI (0.67, 1.52), and it follows from the survival and laryngectomy rate comparisons that the laryngectomy-free survival was not statistically different (p = .95). CONCLUSIONS: There are large differences in the management of glottic cancer between the U.S. and Ontario and no corresponding differences in survival or laryngectomy-free survival. This work highlights a need for more clinical investigation into the relative merits of differing management policies in glottic cancer.
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Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/terapia , Anciano , Femenino , Glotis , Humanos , Laringectomía , Masculino , Persona de Mediana Edad , Ontario , Tasa de Supervivencia , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: Squamous cancers of the upper aerodigestive tract (UADT) are related to the use of tobacco and/or alcohol, and in North America they are more common among the poor. They are usually locoregionally confined at diagnosis, and local treatment with surgery and/or radiation therapy is often curative. This study compares the incidence and survival of this group of diseases in Canada and the U.S., two North American neighbors with many cultural similarities but significant differences in their health care and social programs. METHODS: To describe and compare the case mix, incidence, and outcome of squamous cancers of the UADT in Ontario, Canada, and the U.S., we used the Ontario Cancer Registry (OCR) and the Surveillance, Epidemiology, and End Results (SEER) registries in the U.S. to identify all cases of cancer with International Classification of Disease (ICD) codes 141, 143-9, 160-1, and a subset of 140, which were diagnosed between 1982 and 1994. ICD-O histology codes were placed into clinically relevant groupings, and ICD-9 site codes were grouped into sites as defined by the International Union Against Cancer and the American Joint Committee on Cancer. Age-adjusted incidence rates were calculated for each site. For the SEER registry, race specific incidence rates were also calculated. Observed and expected survival were plotted by site and registry, and from these, relative survival was calculated. Survival was compared during the first 5 years after diagnosis and during the next 5 years among patients who had survived the first 5 years. RESULTS: Of the 16,577 and 42,990 cases identified in the OCR and SEER registries, respectively, squamous cancer was by far the most common histology (94.1% in OCR, 94.6% in SEER) and will form the main subject of this report. The distribution of squamous cancers by site, subsite, age, and gender were remarkably similar in the two populations. Overall, the incidence was about 17% higher in the U.S. than in Ontario, and this difference was seen for all sites except the nasopharynx, which was more common in Ontario. The higher incidence in the U.S. in part reflects the much higher rate for African Americans than for Americans of other ethnic backgrounds. During the first 5 years after diagnosis, when most deaths from UADT cancer occur, there was a significant relative survival difference in favor of the U.S. for cancer of the supraglottis, and in favor of Ontario for cancer of the oral cavity. There was a nonsignificant trend in favor of Ontario for cancer of the nasopharynx. Within the SEER population, for all sites except the nasopharynx, 5-year relative survival was considerably worse for African Americans than for Americans of other ethnic backgrounds. Examination of survival beyond 5 years after diagnosis for patients who had survived the first 5 years revealed that for all sites, the observed survival continued to diverge markedly from the expected survival. The excess mortality ranged from less than 20% for glottic and nasopharyngeal cancers to about 30-40% for oropharyngeal and supraglottic cancers. CONCLUSIONS: Despite remarkable similarities in case mix between the two countries, UADT cancers were more frequent in the SEER population of the U.S. than in Ontario, and this was partly attributable to the much higher incidence among African Americans. Significant differences between the registries in 5-year survival were seen for several sites. African Americans with UADT cancers had much worse prognoses than did Americans of other ethnic backgrounds. Patients who survive their UADT cancer remain at a higher-than-expected risk of death even after they have been cured.
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Neoplasias de la Boca/epidemiología , Neoplasias de Células Escamosas/epidemiología , Neoplasias del Sistema Respiratorio/epidemiología , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Neoplasias de la Boca/mortalidad , Neoplasias de Células Escamosas/clasificación , Neoplasias de Células Escamosas/mortalidad , Ontario , Sistema de Registros , Neoplasias del Sistema Respiratorio/clasificación , Neoplasias del Sistema Respiratorio/mortalidad , Programa de VERF , Factores de Tiempo , Estados UnidosRESUMEN
BACKGROUND: There is a need for a classification system for prognosis based on the TNM system for patients with squamous cell carcinoma of the head and neck such that patient groupings are homogeneous within and heterogeneous between. METHODS: Six hundred fifty-five consecutive patients with invasive squamous cell carcinoma of the head and neck followed prospectively are split into a training set and a test set. Using the training set, the Cox Proportional Hazards Model and the outcome of dead with disease, we created homogeneous prognostic levels (PLs) based on RR. Using the test set, we compare our model to others in the literature. RESULTS: Using the training set, we identified five PLs, and using the test set, we demonstrated that our model is superior to others for both within-group homogeneity and between-group heterogeneity. CONCLUSIONS: A simple classification system can be used to group patients for survival and is valid for future study in prognostication.
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Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/clasificación , Femenino , Neoplasias de Cabeza y Cuello/clasificación , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
This article will present a description of the semi-implicit semantic properties of the Systematized Nomenclature of Human and Veterinary Medicine, also called SNOMED International. It will focus on the formalism of SNOMED and its computational properties using the disease definition as an example. Additional information will be provided in order to convert semi-implicit links found between SNOMED concepts into explicit computational semantic links.