RESUMO
BACKGROUND: HER2-overexpressing breast cancer (BC) is common among young patients and poses a public health burden. Adjuvant anti-HER2/neu therapy with trastuzumab reduces the risk of recurrence and improves survival. METHODS: A web-based survey was sent to 386 physicians of the "TEACH" trial in 2011 to determine access to HER2/neu testing and treatment patterns for HER2-overexpressing BC. RESULTS: There were 151 responders (39%) from 28 countries. Ninety-seven percent reported HER2/neu expression is routinely measured in their institutions by immunohistochemistry (85%), FISH (80%) and other methods (16%). Twenty percent of responders from Asia reported that the test was not routinely available. Forty-eight percent of participants reported instances when adjuvant HER2-directed therapy was recommended to a patient who eventually did not receive it. Reasons for not receiving trastuzumab was cost (73%, p < 0.0001) in low- and middle-income countries and co-morbidities in high-income countries (43%, p = 0.003). CONCLUSIONS: This survey reflects the availability of HER2/neu testing and anti-HER2/neu therapy among physicians who participated in TEACH. A high proportion of women with HER2-overexpressing BC may not receive standard adjuvant therapy due to unavailability of the test and cost of therapy. Despite having some limitations, such as a possible selection bias of participating physicians, variable definitions of access to healthcare among respondents, and changes in trastuzumab availability since 2011, our results demonstrate that access to care and region of practice impact the implementation of cancer treatments.
Assuntos
Neoplasias da Mama/terapia , Países Desenvolvidos/estatística & dados numéricos , Países em Desenvolvimento/estatística & dados numéricos , Padrões de Prática Médica , Antineoplásicos/provisão & distribuição , Antineoplásicos/uso terapêutico , Neoplasias da Mama/química , Ensaios Clínicos Fase III como Assunto , Feminino , Pesquisas sobre Atenção à Saúde , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Humanos , Seguro Saúde/estatística & dados numéricos , Mastectomia Segmentar/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/análise , Trastuzumab/uso terapêuticoRESUMO
PURPOSE: To evaluate the incidence and pattern of hypopituitarism from hypothalamic (HT) and pituitary gland (PG) damage following high-dose conformal fractionated proton-photon beam radiotherapy (PPRT) to the base of skull (BOS) region in adults. The relationship between dose, volume, and PG function is explored. METHODS AND MATERIALS: Between May 1982 to October 1997, 107 adults with non-PG and non-HT neoplasms (predominantly chordoma and chondrosarcomas) of the BOS were treated with PPRT after subtotal resection(s). The median age was 41.2 years (range, 17-75) with 58 males and 49 females. Median prescribed target dose was 68.4 cobalt gray equivalent (CGE) (range, 55.8-79 CGE) at 1.80-1.92 CGE per fraction per day (where CGE = proton Gy x 1.1). The HT and PG were outlined on planning CT scans to allow dose-volume histograms (DVH) analysis. All patients had baseline and follow-up clinical testing of anterior and posterior pituitary function including biochemical assessment of thyroid, adrenal, and gonadal function, and prolactin secretion. RESULTS: The 10-year actuarial overall survival rate was 87%, with median endocrine follow-up time of 5.5 years, thus the majority of patients were available for long-term follow-up. Five-year actuarial rates of endocrinopathy were as follows: 72% for hyperprolactinemia, 30% for hypothyroidism, 29% for hypogonadism, and 19% for hypoadrenalism. The respective 10-year endocrinopathy rates were 84%, 63%, 36%, and 28%. No patient developed diabetes insipidus (vasopressin deficiency). Growth hormone deficiency was not routinely followed in this study. Minimum target dose (Dmin) to the PG was found to be predictive of endocrinopathy: patients receiving 50 CGE or greater at Dmin to the PG experiencing a higher incidence and severity (defined as the number of endocrinopathies occurring per patient) of endocrine dysfunction. Dmax of 70 CGE or greater to the PG and Dmax of 50 CGE or greater to the HT were also predictive of higher rates of endocrine dysfunction. CONCLUSION: Radiation-induced damage to the HT & PG occurs frequently after high-dose PPRT to the BOS and is manifested by anterior pituitary gland dysfunction. Hyperprolactinemia was detected in the majority of patients. Posterior pituitary dysfunction, represented by vasopressin activity with diabetes insipidus, was not observed in this dose range. Limiting the dose to the HT and PG when feasible should reduce the risk of developing clinical hypopituitarism.
Assuntos
Hipotálamo/efeitos da radiação , Hipófise/efeitos da radiação , Radioterapia Conformacional , Neoplasias da Base do Crânio/radioterapia , Adolescente , Adulto , Idoso , Condrossarcoma/mortalidade , Condrossarcoma/radioterapia , Cordoma/mortalidade , Cordoma/radioterapia , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Humanos , Hiperprolactinemia/etiologia , Hiperprolactinemia/mortalidade , Hipogonadismo/etiologia , Hipotireoidismo/etiologia , Hipotireoidismo/mortalidade , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Terapia com Prótons , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Neoplasias da Base do Crânio/mortalidade , Taxa de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Over the past 2 decades both cutaneous melanoma (CM) and non-Hodgkin lymphoma (NHL) incidence rates have increased substantially. One approach to better understanding the etiologic basis for these increases is to examine the risk of NHL in CM survivors and the risk of CM in NHL survivors. METHODS: To explore the possible association between CM and NHL, the authors followed cohorts of CM and NHL patients registered through the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 1996 and identified patients who developed CM after NHL and NHL after CM. The number of observed cases then were compared with the number of expected cases to see if CM survivors were at an increased risk of NHL or if NHL survivors were at an increased risk of CM. RESULTS: Between 1973 and 1996, 54,803 CM patients and 62,597 NHL patients who met the authors' inclusion criteria were identified through SEER. The authors found statistically significant elevated risks of NHL among CM survivors (standardized incidence ratio [SIR], 1.42; 95% confidence interval [CI], 1.23-1.63) and CM among NHL survivors (SIR, 1.75; 95% CI, 1.48-2.07). CONCLUSIONS: These results support an association between CM and NHL. Although detection bias and posttherapy effects may explain part of this association, shared genetic or etiologic factors, such as sunlight exposure, also may play a role.
Assuntos
Linfoma não Hodgkin/epidemiologia , Melanoma/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Neoplasias Cutâneas/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Programa de SEER , Sobreviventes , Estados Unidos/epidemiologiaRESUMO
OBJECTIVES: The aim of our study was to retrospectively compare the patient characteristics, the frequency and pattern of recurrent disease, and survival in patients with stage I bronchioloalveolar carcinoma and adenocarcinoma of the lung. METHODS: Patients with stage I bronchioloalveolar carcinoma or adenocarcinoma other than bronchioloalveolar carcinoma resected between 1984 and 1992 with adequate clinical follow-up were studied. The clinical characteristics of the patients, extent of initial surgical resection, sites of recurrent disease, and overall survival were examined and compared between the 2 groups. The median follow-up for patients with bronchioloalveolar carcinoma and adenocarcinoma was 6.2 years and 5.9 years, respectively. RESULTS: A total of 138 patients were identified. Thirty-three patients had bronchioloalveolar carcinoma and 105 patients had adenocarcinoma. Eleven (33%) of the patients with bronchioloalveolar carcinoma had never smoked cigarettes versus 9 (9%) of the patients with adenocarcinoma (P =.0036). There were no significant differences between patients with bronchioloalveolar carcinoma and adenocarcinoma in sex distribution and overall recurrence rate. Of the 12 patients with recurrent bronchioloalveolar carcinoma, 1 patient (8%) had extrathoracic disease develop at the site of first recurrence compared with 49% of patients with recurrent adenocarcinoma (P <.001). The 5-year survival in patients with bronchioloalveolar carcinoma and in those with adenocarcinoma was 83% and 63%, respectively (P =.04). CONCLUSIONS: Stage I bronchioloalveolar carcinoma is more likely to occur in nonsmokers. Survival is longer in patients with bronchioloalveolar carcinoma. Further research is warranted to define the etiology, clinical course, and molecular abnormalities in patients with bronchioloalveolar carcinoma to generate more effective therapeutic approaches.
Assuntos
Adenocarcinoma Bronquioloalveolar/patologia , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/mortalidade , Adenocarcinoma Bronquioloalveolar/mortalidade , Adenocarcinoma Bronquioloalveolar/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Pneumonectomia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: In patients with cutaneous melanoma, early age at disease onset is characteristic in familial cases and in individuals with multiple primary melanomas. Both subsets of patients with melanoma are at risk for harboring germline CDKN2A or CDK4 mutations. OBJECTIVE: We set out to prospectively determine the prevalence of CDKN2A and CDK4 mutations in a group of young patients with melanoma. DESIGN: We prospectively screened 913 patients over a 6-month period and identified 519 patients with invasive melanomas. We invited 172 patients with melanoma who were younger than 40 years to participate in the study, and 49 patients consented and donated peripheral blood samples. Forty-nine percent (n = 24) of our patients developed cutaneous melanoma before the age of 30 years. SETTING: A melanoma clinic in the Boston, Mass, area. MAIN OUTCOME MEASURE: We used a combination of single-strand conformation analysis and direct sequencing of samples of peripheral blood leukocyte DNA to search for mutations in exons 1alpha, 1beta, 2, and 3 of CDKN2A and in exon 2 of CDK4. RESULTS: The mean and median ages at diagnosis in our group were 30 and 32 years, respectively. Among a group of 49 patients, we detected 1 (2%; 95% confidence interval, 0.07%-10.8%) Met 53 Ile CDKN2A mutation, which was found in a patient with a strong family history of melanoma. This alteration has been previously shown to impair p16 function. One patient had an Ala 148 Thr change in CDKN2A, which has also been shown to be a polymorphism. We also detected a sequence polymorphism (in the 3' untranslated region [3'UTR] of CDKN2A) in 27% of our patients. A similar incidence of this 3'UTR polymorphism was observed in a control population. We found no CDK4 mutations. CONCLUSIONS: Germline CDKN2A and CDK4 mutations are not common in patients who develop melanoma at an early age. This finding contrasts with other cancer-predisposition syndromes, in which there is an increased incidence of germline mutations among young patients. Selection of patients with melanoma for genetic testing based solely on age at onset may not be warranted at the current time.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Quinases Ciclina-Dependentes/genética , Mutação em Linhagem Germinativa/genética , Melanoma/genética , Proteínas Proto-Oncogênicas , Neoplasias Cutâneas/genética , Adolescente , Adulto , Quinase 4 Dependente de Ciclina , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/patologia , Estudos Prospectivos , Sensibilidade e Especificidade , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologiaRESUMO
AIDS Clinical Trial Group (ACTG) randomized trial 021 compared the effect of bactrim versus aerosolized pentamidine (AP) as prophylaxis therapy for pneumocystis pneumonia (PCP) in AIDS patients. Although patients randomized to the bactrim arm experienced a significant delay in time to PCP, the survival experience in the two arms was not significantly different (p = .32). In this paper, we present evidence that bactrim therapy improves survival but that the standard intent-to-treat comparison failed to detect this survival advantage because a large fraction of the subjects either crossed over to the other therapy or stopped therapy altogether. We obtain our evidence of a beneficial bactrim effect on survival by artificially regarding the subjects as dependently censored at the first time the subject either stops or switches therapy; we then analyze the data with the inverse probability of censoring weighted Kaplan-Meier and Cox partial likelihood estimators of Robins (1993, Proceedings of the Biopharmaceutical Section, American Statistical Association, pp. 24-33) that adjust for dependent censoring by utilizing data collected on time-dependent prognostic factors.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Modelos Estatísticos , Pneumonia por Pneumocystis/prevenção & controle , Recusa do Paciente ao Tratamento , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Aerossóis , Algoritmos , Anti-Infecciosos/uso terapêutico , Biometria/métodos , Humanos , Estudos Multicêntricos como Assunto , Pentamidina/administração & dosagem , Pentamidina/uso terapêutico , Pneumonia por Pneumocystis/mortalidade , Probabilidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Taxa de Sobrevida , Combinação Trimetoprima e Sulfametoxazol/uso terapêuticoRESUMO
This paper focuses on the methodology developed for analyzing a multivariate interval-censored data set from an AIDS observational study. A purpose of the study was to determine the natural history of the opportunistic infection cytomeglovirus (CMV) in an HIV-infected individual. For this observational study, laboratory tests were performed at scheduled clinic visits to test for the presence of the CMV virus in the blood and in the urine (called CMV shedding in the blood and urine). The study investigators were interested in determining whether the stage of HIV disease at study entry was predictive of an increased risk for CMV shedding in either the blood or the urine. If all patients had made each clinic visit, the data would be multivariate grouped failure time data and published methods could be used. However, many patients missed several visits, and when they returned, their lab tests indicated a change in their blood and/or urine CMV shedding status, resulting in interval-censored failure time data. This paper outlines a method for applying the proportional hazards model to the analysis of multivariate interval-censored failure time data from a study of CMV in HIV-infected patients.
Assuntos
Análise Multivariada , Modelos de Riscos Proporcionais , Falha de Tratamento , Infecções Oportunistas Relacionadas com a AIDS/sangue , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/urina , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/urina , Infecções por HIV/sangue , Infecções por HIV/complicações , Infecções por HIV/urina , Humanos , Fatores de Risco , Fatores de Tempo , Eliminação de Partículas ViraisRESUMO
BACKGROUND: The high rate of incidence of skeletal complications in women with metastatic breast carcinoma appears to contribute significantly to their morbidity. Although recent trials have demonstrated the efficacy of bisphosphonates in preventing skeletal complications in selected patients, to the authors' knowledge the incidence rate of skeletal complications in an unselected population of women with metastatic breast carcinoma is unknown. The current study was designed to examine the incidence rate of skeletal complications in a large unselected group of women with metastatic breast carcinoma to determine predictors of these complications. METHODS: All women (n = 718) diagnosed with metastatic breast carcinoma between 1981-1991 at the study institution were studied retrospectively. RESULTS: Greater than 50% of the women developed skeletal complications; among these women, 51% had > 1 complication. Approximately 80% of those with bone-limited disease at the time of diagnosis developed complications, as did 60% of those with bone and visceral disease and 21% of those with no bone disease. By univariate analysis, the site of initial metastatic disease, abnormal alkaline phosphatase, and a disease free interval of < 3 years were predictive of skeletal complications. Multivariate analysis revealed that bone involvement at the time of diagnosis was predictive of subsequent skeletal complications. CONCLUSIONS: In this large retrospective study with extensive follow-up, skeletal complications were extremely common and repetitive, although complications predated patient death by >/= 1 year in the group of women presenting with any bone disease. The presence of bone disease at the time of initial presentation was predictive of skeletal complications. In this group of patients, the authors were unable to identify a subgroup with a low rate of skeletal complications.
Assuntos
Doenças Ósseas/etiologia , Neoplasias da Mama/complicações , Carcinoma Ductal de Mama/complicações , Doenças Ósseas/epidemiologia , Osso e Ossos/efeitos da radiação , Osso e Ossos/cirurgia , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Difosfonatos/uso terapêutico , Feminino , Seguimentos , Fraturas Espontâneas/epidemiologia , Fraturas Espontâneas/etiologia , Humanos , Hipercalcemia/epidemiologia , Hipercalcemia/etiologia , Incidência , Pessoa de Meia-Idade , Metástase Neoplásica , Valor Preditivo dos Testes , Lesões por Radiação/epidemiologia , Lesões por Radiação/etiologia , Estudos Retrospectivos , Compressão da Medula Espinal/epidemiologia , Compressão da Medula Espinal/etiologia , Análise de SobrevidaRESUMO
OBJECTIVES: To report the results of a pilot study on the prognostic value of a newly identified actin-binding protein, thymosin beta-15 (Tbeta15), in predicting prostate-specific antigen (PSA) and bone failure in patients with Gleason 6/10 clinically localized prostate cancer. METHODS: Thirty-two patients (median age 70 years) with clinically localized, moderately differentiated (Gleason 6/10) prostate cancer treated by external beam radiotherapy alone (68.4 Gy) with available paraffin blocks at the Massachusetts General Hospital were evaluated for this pilot study. All patients had clinical Stage M0 disease at initial presentation, which was documented by bone scan (T1c-4,NX). Their corresponding biopsy specimens were stained immunohistochemically for Tbeta15, which was then correlated with the clinical outcome in a blinded manner. The median follow-up was 6 years (range 1 to 19) for all of the patients. RESULTS: The outcomes of the 32 patients can be grouped into three categories: patients with no evidence of disease (n = 11), patients with PSA failure without documented bone failure (n = 11), and patients with PSA failure and documented bone failure (n = 10). Tbeta15 staining intensity strongly correlated with clinical outcome. Of those patients whose specimens stained 3+ (strongest staining), 62% developed bone failure compared with 13% of those patients whose specimens stained 1+ (weakest staining) (P = 0.01). The 5-year freedom from PSA failure was only 25% for those patients with 3+ staining compared with 83% for those with 1+ staining (P = 0.02). CONCLUSIONS: The results of this pilot study have demonstrated that Tbeta15 staining intensity may be a potentially important marker to identify high-risk patients with moderately differentiated, clinically localized prostate cancer.
Assuntos
Adenocarcinoma/radioterapia , Adenocarcinoma/secundário , Neoplasias Ósseas/secundário , Neoplasias da Próstata/química , Neoplasias da Próstata/radioterapia , Timosina/análise , Adenocarcinoma/química , Adenocarcinoma/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Prognóstico , Neoplasias da Próstata/patologiaRESUMO
PURPOSE: With the conventional approach of surgery and postoperative radiotherapy for patients with Masaoka Stage III thymoma, progress has been slow for an improvement in the long-term survival rate over the past 20 years. The objective of this study was to evaluate the pattern of failure and survival after surgery and postoperative radiotherapy in Stage III thymoma and search for a new direction for better therapy outcome. METHODS AND MATERIALS: Between 1975 and 1993, 111 patients with thymoma were treated at Massachusetts General Hospital. Of these, 32 patients were determined to have Masaoka Stage III thymoma. The initial treatment included surgery for clinically resectable disease in 25 patients and preoperative therapy for unresectable disease in 7 patients. Surgical procedure consisted of thymectomy plus resection of involved tissues. For postoperative radiotherapy (n = 23), radiation dose consisted of 45-50 Gy for close resection margins, 54 Gy for microscopically positive resection margins, and 60 Gy for grossly positive margins administered in 1.8 to 2.0 Gy of daily dose fractions, 5 fractions a week, over a period of 5 to 6.6 weeks. In preoperative radiotherapy, a dose of 40 Gy was administered in 2.0 Gy of daily dose fractions, 5 days a week. For patients with large tumor requiring more than 30% of total lung volume included in the target volume (n = 3), a preoperative radiation dose of 30 Gy was administered and an additional dose of 24-30 Gy was given to the tumor bed region after surgery for positive resection margins. RESULTS: Patients with Stage III thymoma accounted for 29% (32/111 patients) of all patients. The median age was 57 years with a range from 27 to 81 years; gender ratio was 10:22 for male to female. The median follow-up time was 6 years. Histologic subtypes included well-differentiated thymic carcinoma in 19 (59%), high-grade carcinoma in 6 (19%), organoid thymoma in 4 (13%), and cortical thymoma in 3 (9%) according to the Marino and Müller-Hermelink classification. The overall survival rates were 71% and 54% at 5 and 10 years, respectively. Ten of the 25 patients who were subjected to surgery as initial treatment were found to have incomplete resection by histopathologic evaluation. The 5- and 10-year survival rates were 86% and 69% for patients (n = 15) with clear resection margins as compared with 28% and 14% for those (n = 10) with incomplete resection margins even after postoperative therapy, p = 0.002. Survival rates at 5 and 10 years were 100% and 67% for those with unresectable disease treated with preoperative radiation (n = 6) and subsequent surgery (n = 3). Recurrence was noted in 12 of 32 patients and 11 of these died of recurrent thymoma. Recurrences at pleura and tumor bed accounted for 77% of all relapses, and all pleural recurrences were observed among the patients who were treated with surgery initially. CONCLUSION: Incomplete resection leads to poor results even with postoperative radiotherapy or chemoradiotherapy in Stage III thymoma. Pleural recurrence is also observed more often among patients treated with surgery first. These findings suggest that preoperative radiotherapy or chemoradiotherapy may result in an increase in survival by improving the rate of complete resection and reducing local and pleural recurrences.
Assuntos
Timoma/radioterapia , Timoma/cirurgia , Neoplasias do Timo/radioterapia , Neoplasias do Timo/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Timoma/mortalidade , Neoplasias do Timo/mortalidade , Falha de TratamentoRESUMO
Abnormal serotonergic regulation in bulimia nervosa is thought to contribute to recurrent binge eating, depressed mood, and impulsivity. To follow-up on previous studies showing decreased neuroendocrine responses in symptomatic patients, this study assessed serotonin-mediated prolactin responses in individuals who had remitted from bulimia nervosa. Subjects included 21 women with a history of bulimia nervosa and 21 healthy female controls, as well as an additional comparison group of 19 women with current bulimia nervosa. Placebo-controlled neuroendocrine response studies utilized a single oral dose (60 mg) of the indirect serotonin agonist d,l-fenfluramine. For the bulimia nervosa remitted group, the fenfluramine-stimulated elevation in serum prolactin concentration was not significantly different from the response in healthy controls, but was significantly larger than the response in patients with current bulimia nervosa (p < .01). These findings suggest that diminished serotonergic neuroendocrine responsiveness in bulimia nervosa reflects a state-related abnormality. The results are discussed in relationship to recent reports indicating that some alterations in central nervous system serotonin regulation may persist in symptomatically recovered individuals.
Assuntos
Aminoácidos/sangue , Bulimia/sangue , Bulimia/reabilitação , Fenfluramina , Prolactina/sangue , Agonistas do Receptor de Serotonina , Serotonina/fisiologia , Adulto , Feminino , Fenfluramina/farmacologia , Hormônios/sangue , Humanos , Placebos , Prolactina/metabolismo , Valores de Referência , Agonistas do Receptor de Serotonina/farmacologia , Triptofano/sangueRESUMO
Non-parametric tests of independence, as well as accompanying measures of association, are essential tools for the analysis of bivariate data. Such tests and measures have been developed for uncensored and right censored failure time data, but have not been developed for interval censored failure time data. Bivariate interval censored data arise in AIDS studies in which screening tests for early signs of viral and bacterial infection are done at clinic visits. Because of missed clinic visits, the actual times of first positive screening tests are interval censored. To handle such data, we propose an extension of Kendall's coefficient of concordance. We apply it to data from an AIDS study that recorded times of shedding of cytomegalovirus (CMV) and times of colonization of mycobacterium avium complex (MAC). We examine the performance of our proposed measure through a simulation study.
Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Simulação por Computador , Estatísticas não Paramétricas , Síndrome da Imunodeficiência Adquirida/complicações , Contagem de Linfócito CD4 , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/urina , Fezes/microbiologia , Humanos , Complexo Mycobacterium avium/isolamento & purificação , Infecção por Mycobacterium avium-intracellulare/complicações , Escarro/microbiologiaRESUMO
We derive a non-parametric maximum likelihood estimator for bivariate interval censored data using standard techniques for constrained convex optimization. Our approach extends those taken for univariate interval censored data. We illustrate the estimator with bivariate data from an AIDS study.
Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Funções Verossimilhança , Estatísticas não Paramétricas , Síndrome da Imunodeficiência Adquirida/complicações , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/urina , Fezes/microbiologia , Humanos , Complexo Mycobacterium avium/isolamento & purificação , Infecção por Mycobacterium avium-intracellulare/complicações , Escarro/microbiologiaRESUMO
The latency time of an infectious disease is defined as the time from infection to disease onset. This paper applies the proportional hazards model to estimate the effect of covariates on latency when the time of disease onset is exact or right-censored but the time of infection is interval-censored. We use a Monte Carlo EM algorithm to estimate parameters of the joint distribution of infection times and latency times. At each EM iteration, exact infection times are multiply imputed from the density determined by the parameters of the infection and latency time distributions. The methodology is tested using a simulation study and is applied to data from a cohort of haemophiliacs with HIV disease.
Assuntos
Soropositividade para HIV/complicações , Modelos Biológicos , Modelos de Riscos Proporcionais , Algoritmos , Estudos de Coortes , Simulação por Computador , Infecções por HIV/complicações , Infecções por HIV/imunologia , Soropositividade para HIV/imunologia , Hemofilia A/complicações , Hemofilia A/imunologia , Humanos , Método de Monte Carlo , Fatores de TempoRESUMO
Clinical trials often assess therapeutic benefit on the basis of an event such as death or the diagnosis of disease. Usually, there are several additional longitudinal measures of clinical status which are collected to be used in the treatment comparison. This paper proposes a simple non-parametric test which combines a time to event measure and a longitudinal measure so that a substantial treatment difference on either of the measures will reject the null hypothesis. The test is applied on AIDS prophylaxis and paediatric trials.
Assuntos
Síndrome da Imunodeficiência Adquirida/mortalidade , Ensaios Clínicos como Assunto/estatística & dados numéricos , Resultado do Tratamento , Fármacos Anti-HIV/uso terapêutico , Anti-Infecciosos/uso terapêutico , Antifúngicos/uso terapêutico , Candidíase/prevenção & controle , Criança , Pré-Escolar , Clotrimazol/uso terapêutico , Dapsona/uso terapêutico , Didanosina/uso terapêutico , Quimioterapia Combinada , Fluconazol/uso terapêutico , Cabeça/crescimento & desenvolvimento , Humanos , Estudos Longitudinais , Pentamidina/uso terapêutico , Pneumonia por Pneumocystis/prevenção & controle , Estatísticas não Paramétricas , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Zidovudina/uso terapêuticoRESUMO
A Phase I study of paclitaxel and doxorubicin administered as concurrent 96-h continuous i.v. infusion was performed to determine the maximum tolerated dose (MTD), principal toxicities, and pharmacokinetics of this combination in women with relapsed epithelial ovarian cancer. The paclitaxel dose was fixed at 100 mg/m2 (25 mg/m2/day for 4 days). The dose of doxorubicin was escalated from 30 mg/m2 (7.5 mg/m2/day for 4 days) in increments of 10 mg/m2 until dose-limiting toxicity was observed. All patients received granulocyte colony-stimulating factor 5 microg/kg/day prophylactically. Apparent steady-state plasma levels of both drugs were determined in the final cohort of patients treated at the MTD. A total of 17 patients received 52 cycles of therapy. The median age was 58 years, and all patients had previously received one to five different regimens (median, 2) of chemotherapy, including both platinum and paclitaxel. The treatment was tolerated well, with grade 1-2 nausea being the most frequent side effect (73% of cycles). Anemia, neutropenia, thrombocytopenia, and mucositis became dose limiting at the fourth dose level, defining the MTD of doxorubicin in this regimen as 50 mg/m2. There were four partial responses and one complete response in 15 evaluable patients. Apparent steady-state plasma concentrations (mean +/- SD) of paclitaxel and doxorubicin in the three patients treated at the MTD were 33.9 +/- 12.5 nM and 15.7 +/- 1.3 nM, respectively. Paclitaxel and doxorubicin by continuous infusion is a well-tolerated and active chemotherapy regimen for recurrent ovarian cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos de Coortes , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Recidiva , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: To determine the impact of clinical presentation variables on the management and survival of patients with gastrointestinal (GI) tract carcinoid tumors. METHODS: A 20-year (1975-1995) retrospective analysis of 150 patients with GI tract carcinoid tumors at the Massachusetts General Hospital was conducted. Median follow-up was 66 months (range 1-378). Survival estimates for prognostic factors were calculated using Kaplan-Meier product limit estimators, with death from carcinoid as the outcome. Univariate analyses for each factor were obtained using a log-rank test, and multivariate survival analysis was performed. RESULTS: All but two patients underwent surgical intervention with the intent to cure (90%) or debulk the tumor (9%). Mean age at presentation was 55 +/- 18 years (range 11-90). There was a slight female/male predominance (80:70). Symptoms were nonspecific; the most common were abdominal pain (40%), nausea and vomiting (29%), weight loss (19%), and GI blood loss (15%). Incidental carcinoids, discovered at the time of another procedure, occurred in 40% of patients and were noted at multiple sites throughout the GI tract. The distribution of tumors was ileojejunum (37%), appendix (31 %), colon (13%), rectum (12%), stomach (4%), duodenum (1.3%), and Meckel's diverticulum (1.3%). Of the 27 patients with documented liver metastases, carcinoid syndrome developed in only 13 patients (48%), manifested by watery diarrhea (100%), upper body flushing (70%), asthma (38%), and tricuspid regurgitation (23%). All 13 patients with carcinoid syndrome had elevated levels of 5-HIAA, but the absolute levels did not correlate with the severity of symptoms. An additional 11 patients, 3 without liver metastases, had elevated levels of 5-HIAA without any evidence of carcinoid syndrome. Multicentric carcinoid tumors occurred in 15 patients (10%), and all but one of these tumors were centered around the ileocecal valve. There was no difference in the incidence of liver metastases between solitary (18%) and multicentric carcinoids (20%). Synchronous noncarcinoid tumors were present in 33 patients (22%), and metachronous tumors developed in an additional 14 patients (10%) in follow-up. Age and tumor size, depth, and location were significant predictors of metastases. By multivariate analysis, age > or = 50 years, metastases, and male gender were statistically significant predictors of death. CONCLUSIONS: Gastrointestinal tract carcinoid tumors have a nonspecific clinical presentation, except in the case of the carcinoid syndrome. Surgical resection is the treatment of choice for improving survival. Surgically treated patients with carcinoid tumor have an overall favorable 83% 5-year survival rate.
Assuntos
Tumor Carcinoide/mortalidade , Neoplasias Gastrointestinais/mortalidade , Tumor Carcinoide/complicações , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/secundário , Feminino , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/diagnóstico , Humanos , Masculino , Síndrome do Carcinoide Maligno/epidemiologia , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
HYPOTHESIS: Merkel cell carcinoma is a rare dermal neuroendocrine carcinoma whose optimal treatment and prognostic factors are poorly defined. We hypothesize that high-risk patients with Merkel cell carcinoma are best treated with multimodality therapy. DESIGN: A retrospective review of all patients (N = 33) with Merkel cell carcinoma treated at the Massachusetts General Hospital from January 1, 1980, to August 24,1997. Median follow-up time was 37 months (range, 6-157 months). PATIENTS: Adequate data for evaluation were available for 31 patients. Male to female distribution was 14 men and 17 women, with a median patient age of 68 years. MAIN OUTCOME MEASURE: Stage at presentation; factors associated with recurrence; and the effects of surgery, radiation therapy (XRT), and chemotherapy on recurrence, salvage, and survival rates. RESULTS: There were 12 extremity, 11 head and neck, and 8 truncal tumors. There were 22 isolated primary tumors, 8 with additional clinically positive lymph nodes, and 1 with distant disease. Therapy was local excision with or without XRT in 19 patients, local resection and lymphadenectomy with or without XRT in 8 patients, and XRT alone in 4 patients with head and neck tumors. Fifteen patients developed recurrences (7 local, 8 nodal, and 10 distant). Median time to recurrence was 8 months (range, 3-48 months). There were 7 tumor-related deaths, 6 of which were associated with truncal lesions (P<.001). No locoregional recurrences occurred in patients with margins of resection of 2 cm or greater or adequate XRT. A multivariate analysis selected truncal location (P = .005) and nodal disease (P = .05) as predictors of mortality. Remission was possible in 5 patients with locoregional and 2 patients with distant recurrences. CONCLUSIONS: Merkel cell carcinoma is an aggressive dermal cancer with frequent nodal metastases; truncal tumors have the worst prognosis. Locoregional recurrence correlates with inadequate margins and lack of XRT, but remission is possible with multimodality therapy.
Assuntos
Carcinoma de Célula de Merkel/terapia , Neoplasias Cutâneas/terapia , Idoso , Carcinoma de Célula de Merkel/mortalidade , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidade , Taxa de Sobrevida , Resultado do TratamentoRESUMO
This paper develops methodology for estimation of the effect of a binary time-varying covariate on failure times when the change time of the covariate is interval censored. The motivating example is a study of cytomegalovirus (CMV) disease in patients with human immunodeficiency virus (HIV) disease. We are interested in determining whether CMV shedding predicts an increased hazard for developing active CMV disease. Since a clinical screening test is needed to detect CMV shedding, the time that shedding begins is only known to lie in an interval bounded by the patient's last negative and first positive tests. In a Cox proportional hazards model with a time-varying covariate for CMV shedding, the partial likelihood depends on the covariate status of every individual in the risk set at each failure time. Due to interval censoring, this is not always known. To solve this problem, we use a Monte Carlo EM algorithm with a Gibbs sampler embedded in the E-step. We generate multiple completed data sets by drawing imputed exact shedding times based on the joint likelihood of the shedding times and event times under the Cox model. The method is evaluated using a simulation study and is applied to the data set described above.