RESUMO
BACKGROUND: Immune checkpoint inhibitors (CPIs) have not been shown to be active in well-differentiated neuroendocrine tumors (NETs), with response rates <5%. Lenvatinib is a multitargeted tyrosine kinase inhibitor which binds to vascular endothelial growth factor and fibroblast growth factor receptors and has demonstrated efficacy in pancreatic and gastrointestinal NETs [44% and 16% objective radiographic response rate (ORR), respectively]. The combination of antiangiogenic and CPI therapies can be synergistic. We therefore evaluated the combination of lenvatinib and pembrolizumab in well-differentiated gastrointestinal (GI) and thoracic NETs. PATIENTS AND METHODS: A prospective, phase II trial evaluated patients with advanced GI/thoracic NETs (pancreatic NETs were excluded due to high response rate of lenvatinib monotherapy in this patient population), with evidence of progression within 8 months of study entry and at least two prior lines of systemic therapy. Patients received lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or progression of disease. Primary endpoint was objective response rate, and an interim analysis was planned once 20 patients were enrolled. Four ORRs were required to continue enrollment. RESULTS: Twenty patients were enrolled on protocol from April 2021 to January 2022 (nine small intestine, five lung, two thymic, two unknown primary, one cecal, one presacral primaries). Two patients (10%) achieved a partial response (atypical lung and small intestinal primaries). Median progression-free survival (PFS) was 8 months (95% confidence interval 5.8-10.2 months). Twelve (60%) patients experienced probably or definitely associated grade 3 adverse events (10 hypertension). Fourteen patients (70%) required dose reductions or discontinued one of the medications. Two patients discontinued treatment before radiographic assessment. CONCLUSIONS: The combination of pembrolizumab and lenvatinib did not show sufficient response in patients with NETs to warrant continued enrollment on trial.
Assuntos
Anticorpos Monoclonais Humanizados , Tumores Neuroendócrinos , Compostos de Fenilureia , Quinolinas , Humanos , Quinolinas/uso terapêutico , Quinolinas/farmacologia , Masculino , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/farmacologia , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Tumores Neuroendócrinos/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologiaAssuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Metotrexato/administração & dosagem , Tacrolimo/administração & dosagem , Doadores não Relacionados , Adulto , Aloenxertos , Anticorpos Monoclonais Humanizados/farmacocinética , Doença Enxerto-Hospedeiro/etiologia , Humanos , Metotrexato/farmacocinética , Pessoa de Meia-Idade , Tacrolimo/farmacocinéticaRESUMO
Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60âmg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60âmg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response.
Assuntos
Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Somatostatina/análogos & derivados , Adulto , Idoso , Preparações de Ação Retardada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Receptores de Somatostatina/metabolismo , Somatostatina/administração & dosagemRESUMO
BACKGROUND: The liver is the predominant site of metastases among patients with advanced neuroendocrine tumors (NETs). Prior retrospective studies have reported high response rates in patients treated with transarterial embolization (TAE). NETs are highly vascular and are known to express vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR). We hypothesized that administration of sunitinib, a VEGFR inhibitor, following TAE would extend progression-free survival (PFS). PATIENTS AND METHODS: Patients with metastatic NETs to the liver underwent a series of selective TAEs followed by sunitinib (until disease progression or maximum of 12 months). Radiographic response (by RECIST), survival, and safety parameters were monitored. RESULTS: Thirty-nine patients were enrolled. The overall response rate was 72% [95% confidence interval (CI), 0.58-0.86]. Median PFS was 15.2 months. Rates of overall survival (OS) at 1 and 4 years were 95% (95% CI, 0.88-1.00) and 59% (95% CI, 0.38-0.80), respectively. A significant 34% rise in serum VEGF was observed following the initial TAE (P = 0.03). CONCLUSIONS: Hepatic TAE is a highly active treatment option for patients with metastatic NETs to the liver. Embolization stimulates release of VEGF into the circulation. Sunitinib, an oral VEGFR inhibitor, can be safely administered following embolization. The high rates of PFS and OS associated with this sequence of therapies are encouraging.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Embolização Terapêutica , Artéria Hepática , Indóis/uso terapêutico , Neoplasias Intestinais/terapia , Neoplasias Hepáticas/terapia , Pirróis/uso terapêutico , Resinas Acrílicas/uso terapêutico , Adulto , Idoso , Inibidores da Angiogênese/farmacologia , Intervalo Livre de Doença , Feminino , Gelatina/uso terapêutico , Humanos , Indóis/farmacologia , Neoplasias Intestinais/sangue , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/patologia , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Tumores Neuroendócrinos , Modelos de Riscos Proporcionais , Pirróis/farmacologia , Estatísticas não Paramétricas , Sunitinibe , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Patients on systemic glucocorticoids for GVHD after hematopoietic cell transplant are susceptible to invasive fungal infections (IFI), which greatly contribute to morbidity and mortality. We evaluated the efficacy of prophylactic treatment options (voriconazole or fluconazole vs itraconazole) for IFI by performing a retrospective review of patients on glucocorticoids for GVHD who were administered voriconazole (n=97), fluconazole (n=36) or itraconazole (n=36). IFI developed in 7/72 (10%) patients on fluconazole/itraconazole vs 2/97 (2%) on voriconazole (P=0.03) within the first 100 days of glucocorticoids. Five (7%) patients developed Aspergillus IFI on fluconazole/itraconazole, compared with none on voriconazole (0%) (P=0.008); Aspergillus IFI resulted in death in all five patients. We found that IFI occurred in patients who received an initial dose of at least 2 mg/kg/day of prednisone or equivalent; when the analysis was restricted to these patients, the hazard ratio (0.39; 95% confidence interval: 0.08-1.86) was consistent with a protective effect of voriconazole compared with fluconazole/itraconazole, although this subset analysis did not reach significance. OS at 100 days after start of glucocorticoids was 77% in patients administered fluconazole/itraconazole and 85% in those administered voriconazole (P=0.22). Our results suggest that voriconazole is more effective than fluconazole/itraconazole in preventing IFI, especially aspergillosis, in patients receiving glucocorticoids post transplant.
Assuntos
Antifúngicos/uso terapêutico , Glucocorticoides/efeitos adversos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Micoses/prevenção & controle , Pirimidinas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Quimioprevenção , Feminino , Fluconazol/uso terapêutico , Humanos , Itraconazol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , VoriconazolRESUMO
OBJECTIVES: To measure the efficacy and toxic effects of our chemoradiotherapy regimen by means of response and survival in patients with advanced squamous cell carcinoma of the head and neck (HNSCC) for organ preservation in resectable disease or palliation in unresectable disease. DESIGN: All patients underwent evaluation by the multidisciplinary head and neck cancer team, with pathological diagnosis and staging. All patients underwent assessment for response to therapy using results of physical examination and radiologic imaging. Patients were followed up at 3-month intervals for a planned period of 5 years. SETTING: Academic center. PATIENTS: Thirty-eight previously untreated patients with newly diagnosed HNSCC were treated from June 1, 1996, through December 31, 1998, of whom 20 had resectable and 18 had unresectable tumors. INTERVENTION: Patients received intravenous cisplatin, 100 mg/m(2) for 1 hour on days 1 and 29; a 24-hour continuous infusion of fluorouracil, 1000 mg/m(2) on days 1 through 4 and 29 through 32; and radiation therapy, 150 rad twice daily for 12 days. The patients were given a 7- to 10-day break, and radiation therapy was restarted on day 29 for 12 additional days (total dose, 7200 rad). MAIN OUTCOME MEASURES: Complete, partial, and total response rates; disease-free survival; overall survival; and toxic effects. RESULTS: Toxic effects of treatment were moderately severe, including grades III to IV mucositis (89%), neutropenia (71%), and renal toxic effects (8%). In the 18 patients in the unresectable group, complete response in the 17 primary tumors and 15 cervical nodal metastases was achieved in 12 (71%) and 9 (60%), respectively; in the 20 patients undergoing organ preservation, complete response rates were 100% in the 23 primary tumors and 15 cervical nodal metastases. Complete response for all 38 patients was achieved in 31 (82%). In the unresectable group, the Kaplan-Meier relapse-free survival estimate is 56%, with follow-up from 29 to 45 months. In the organ preservation group, 75% of patients are alive without disease, and 8 have been followed up for 36 to 48 months. Of the 5 patients who have died, only 2 died of disease, with recurrences at 13.0 and 16.5 months. CONCLUSIONS: Chemoradiotherapy consisting of cisplatin, fluorouracil, and twice-daily external beam radiation is highly effective in achieving durable complete responses in patients with resectable HNSCC undergoing organ preservation and patients with unresectable HNSCC undergoing palliation. Toxic effects of this regimen were moderate to severe.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Cuidados Paliativos , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Cisplatino/administração & dosagem , Terapia Combinada , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
RATIONALE AND OBJECTIVES: The authors performed this study to evaluate the factors affecting phantom image score at the annual inspection of mammography facilities. MATERIALS AND METHODS: In 1997, three U.S. Food and Drug Administration (FDA)-trained inspectors performed inspections of all mammography facilities in North Carolina. All federal and state inspection data were collected and evaluated by using linear regression analysis. Factors affecting the American College of Radiology phantom scores were assessed. RESULTS: Phantom score was affected by inspector identity, view box luminance, and optical density. All of these factors had a statistically significant effect on mass score (P < .05). Inspector identity yielded a statistically significant effect on speck group score, fibril score, and total score. Luminance yielded a statistically significant effect on both speck group score and total score. CONCLUSION: Phantom scoring should be automated to allow for more consistent interobserver scoring. In addition, radiology facilities can improve the likelihood of receiving a passing phantom score by reducing the ambient light and increasing the view box luminance in the location where the images are evaluated and the phantom is scored routinely. Radiologists should also consider increasing phantom and clinical image optical density to allow for improved phantom testing outcomes.
Assuntos
Mamografia/instrumentação , Imagens de Fantasmas , Doenças Mamárias/diagnóstico , Feminino , Humanos , Modelos Lineares , Mamografia/normas , North Carolina , Controle de Qualidade , Estados Unidos , United States Food and Drug AdministrationRESUMO
To evaluate the effect of daily beta-carotene (30 mg) versus placebo over a 2-year period on cervical intraepithelial neoplasia (CIN) 2 and 3 lesions. Human papillomavirus (HPV) typing was done to determine whether lesion regression was related to HPV. Micronutrient levels were measured to determine whether levels were predictive of regression. Variables that influence the risk of HPV infection and CIN, such as cigarette smoking and sexual behavior, were evaluated. Women were randomized to beta-carotene or placebo, with cytology and colposcopy every 3 months. Cervical biopsies were performed before treatment and after 6 and 24 months to evaluate response. Persistence of or progression to CIN 3 resulted in removal from the study, whereas treatment continued for 2 years on all others. The presence and type of HPV was determined by PCR. Response was defined as an improvement in CIN by 2 grades. Mantel-Haenszel chi(2) test was used to analyze response to treatment. Fisher's exact test was used to determine the effect of HPV and CIN grade on response Wilcoxon's rank-sum tests were used to compare micronutrient levels between groups. Twenty-one of 124 enrolled women were not randomized because they either moved, became pregnant, voluntarily withdrew, or the pathological review of their initial cervical biopsies did not confirm CIN 2 or 3. Of the remaining 103 women, 33 experienced lesion regression, 45 had persistent or progressive disease, and 25 women did not complete the study and were considered nonresponders in the final analysis. The overall regression rate (32%) was similar between treatment arms and when stratified for CIN grade. Data on 99 women with HPV typing showed that 77% were HPV-positive and 23% HPV-negative at enrollment. HPV-positive lesions were subdivided into indeterminate-, low-, and high-risk categories; the response rate was highest for women with no HPV detected (61%), lower for indeterminate/low-risk (30%), and lowest for high-risk (18%; P =.001). CIN regression was negatively correlated with retinol levels. In conclusion, beta-carotene does not enhance the regression of high-grade CIN, especially in HPV-positive subjects.
Assuntos
Antioxidantes/administração & dosagem , Displasia do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , beta Caroteno/administração & dosagem , Administração Oral , Adolescente , Adulto , Biópsia por Agulha , Suplementos Nutricionais , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Modelos Logísticos , Assistência de Longa Duração , Pessoa de Meia-Idade , Probabilidade , Valores de Referência , Índice de Gravidade de Doença , Resultado do Tratamento , Neoplasias do Colo do Útero/diagnóstico , Esfregaço Vaginal , Displasia do Colo do Útero/diagnósticoRESUMO
BACKGROUND: A modified Phase I/II trial was conducted evaluating the incorporation of three-dimensional conformal radiation therapy into a strategy of sequential and concurrent carboplatin/paclitaxel in Stage III unresectable nonsmall cell lung carcinoma (NSCLC). The dose of thoracic conformal radiation therapy (TCRT) from 60 to 74 gray (Gy) was increased. Endpoints included response rate, toxicity, and survival. METHODS: Sixty-two patients with unresectable Stage III NSCLC were included. Patients received 2 cycles of induction carboplatin (area under the concentration curve [AUC], 6) and paclitaxel (225 mg/m(2) over 3 hours) every 21 days. On Day 43, concurrent TCRT and weekly (x 6) carboplatin (AUC, 2) and paclitaxel (45 mg/m(2)/3 hours) were initiated. The TCRT dose was escalated from 60 to 74 Gy in 4 cohorts (60, 66, 70, and 74 Gy). RESULTS: The response rate to induction carboplatin/paclitaxel was 40%. Eight patients (13%) progressed on the induction phase. No dose-limiting toxicity was observed during the escalation of the TCRT dose from 60 to 74 Gy. The major toxicity was esophagitis, however, only 8% developed Grade 3/4 esophagitis using Radiation Therapy Oncology Group criteria. The overall response rate was 52%. Survival rates at 1, 2, 3, and 4 years were 71%, 52%, 40%, and 36%, respectively, with a median survival of 26 months. The 1-, 2-, and 3-year progression free survival probabilities were 47%, 35%, and 29%, respectively. CONCLUSIONS: Incorporation of TCRT with sequential and concurrent carboplatin/paclitaxel is feasible, and dose escalation of TCRT to 74 Gy is possible with acceptable toxicity. Overall response and survival rates are encouraging. Both locoregional and distant failure remain problematic in this population of patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Radioterapia Conformacional , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Taxa de Sobrevida , Falha de TratamentoRESUMO
A study was conducted to test the hypothesis that oxidative DNA damage caused by exposure to organochlorines is an important risk factor in breast cancer. This is the first study that evaluates this hypothesis by measuring 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, polychlorinated biphenyl (PCB) congeners, and isomers of bis (4-chlorophenyl)-1,1,1-trichloroethane (DDT) and bis (4-chlorophenyl)-2,2,2-dichloroethane (DDE) in cancerous and noncancerous tissue. We measured these compounds in 44 primary tumors (cancerous) and 21 benign breast biopsy (noncancerous) tissues. Overall, no significant differences were observed in the level of the organochlorines between the tissues. The median concentration for 8-OHdG was 10.5 fmol/mg DNA (1.7/10(5) deoxyguanosine residues), and 8.5 fmol/mg DNA (1.4/10(5) deoxyguanosine residues) in cancerous and noncancerous tissue, respectively. These values are similar to background levels. No significant differences were observed in 8-OHdG levels in cancerous versus noncancerous tissue, and no correlation was demonstrated between the organochlorines and 8-OHdG. The data thus do not support the hypothesis that oxidative DNA damage caused by exposure to organochlorines is an important risk factor in breast cancer.
Assuntos
Neoplasias da Mama/induzido quimicamente , DDT/efeitos adversos , Dano ao DNA , Desoxiguanosina/análise , Diclorodifenil Dicloroetileno/efeitos adversos , Poluentes Ambientais/efeitos adversos , Inseticidas/efeitos adversos , Estresse Oxidativo , Bifenilos Policlorados/efeitos adversos , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Biomarcadores/análise , Neoplasias da Mama/fisiopatologia , DDT/análise , Desoxiguanosina/análogos & derivados , Diclorodifenil Dicloroetileno/análise , Exposição Ambiental , Poluentes Ambientais/análise , Feminino , Humanos , Inseticidas/análise , Bifenilos Policlorados/análise , Fatores de RiscoRESUMO
OBJECTIVE: The purpose of this study was to have a series of screening mammograms from routine practice, including false-negative results, reviewed by peer community-based experienced radiologists to determine the percentage of these false-negative findings that might be considered detectable. MATERIALS AND METHODS: All screening cases for 1997 and 1998 were identified from the Carolina Mammography Registry. Mammographic assessments from community mammography practices were linked with population-based cancer outcomes. The findings of four community-based radiologists who reviewed the mammograms of 339 asymptomatic women were 93 false-negatives, 180 true-negatives, and 66 false-positives. The percentage of false-negative, true-negative and false-positive findings on breast films that reviewers evaluated was determined. The findings of the reviewers were compared with the original interpreting radiologists' assessments. RESULTS: The overall breast-specific workup rate by the reviewing radiologists was 21%. The average workup rate for the false-negative findings was 42% (range, 35-51%). Adjusting for the 13% workup rate in the cancer-free breasts, the percentage of false-negative findings that were detectable was estimated to be 29%. CONCLUSION: This peer review of screening mammograms from a population-based screening registry estimated a missed detectable cancer rate of 29%. Thus, 71% of cancers missed at screening would not have been worked up by peers in the same community.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Mamografia/estatística & dados numéricos , Programas de Rastreamento/estatística & dados numéricos , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/epidemiologia , Erros de Diagnóstico , Reações Falso-Negativas , Feminino , Humanos , Pessoa de Meia-Idade , North Carolina , Revisão por ParesRESUMO
OBJECTIVE: The performance of screening mammography is measured mainly by its sensitivity, positive predictive value, and cancer detection rate. Recall rates are also suggested as a surrogate measure. The main objective of this study was to measure the effect on sensitivity and positive predictive value as recall rates increase in the community practice of mammography. MATERIALS AND METHODS: Mammography and pathology data are linked in the Carolina Mammography Registry, a population-based registry of screening mammography. Our mammography database is created from prospectively collected data from mammography facilities; the data include information on the woman and the imaging studies. Our pathology database is created from prospectively collected breast pathology data received from pathology sites and the Central Cancer Registry. Women in the registry who were 40 years old and older and who underwent screening mammography between January 1994 and June 1998 were included. "Recall rate" was defined as the percentage of screening studies for which further workup was recommended by the radiologist. RESULTS: The study included 215,665 screening mammograms. The mean age of the women was 56 years. The recall rates of the average practice ranged from 1.9% to 13.4%. Sensitivity rose from a mean of 65% in the lowest recall rates to 80.2% at the highest level of recall rates. The positive predictive value of screening decreased from 7.2% in the lowest level of recall to 3.3% in the highest. As recall rates increased, sensitivity increased very little beyond a recall rate of 4.8%, and positive predictive value began decreasing significantly at a recall rate of 5.9%. CONCLUSION: Practices with recall rates between 4.9% and 5.5% achieve the best trade-off of sensitivity and positive predictive value.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Mamografia/estatística & dados numéricos , Programas de Rastreamento/estatística & dados numéricos , Adulto , Idoso , Mama/patologia , Neoplasias da Mama/patologia , Bases de Dados Factuais , Erros de Diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , North Carolina , Valor Preditivo dos Testes , Estudos Prospectivos , Sistema de Registros/estatística & dados numéricosRESUMO
To assess the validity of retrospective medical chart review as a method of classifying prostate-specific antigen (PSA) tests as screening or diagnostic services, we reviewed PSA tests ordered at a university hospital (n = 95). PSA tests were reviewed by four raters: medicine resident (RES), oncologist (ONC), urologist (UR), medicine attending (GM)-and the physician who ordered the PSA test (ATTEND) using predefined standardized criteria. Agreement rates by individual rater and ATTEND were 0.79 (GM), 0.80 (ONC), 0.74 (UR), 0.83 (RES), for a composite percent agreement of 0.79. ATTEND incorrectly classified seven tests; exclusion of these tests raised agreement rates to 0.86 (GM), 0.86 (ONC), 0.80 (UR), 0.90 (RES), for a group composite percent agreement of 0.86. Of note, two raters had higher agreement rates when evaluating screening PSA tests than when evaluating diagnostic PSA tests. Standardized criteria applied to medical charts provide a valid method of retrospectively classifying PSA tests.
Assuntos
Grupos Diagnósticos Relacionados/normas , Programas de Rastreamento/normas , Antígeno Prostático Específico , Neoplasias da Próstata/diagnóstico , Estudos Retrospectivos , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , North Carolina , Neoplasias da Próstata/prevenção & controleRESUMO
The consequences of the rapid 3-phosphorylation of inositol 1,4,5-trisphosphate (IP(3)) to produce inositol 1,3,4,5-tetrakisphosphate (IP(4)) via the action of IP(3) 3-kinases involve the control of calcium signals. Using green fluorescent protein constructs of full-length and truncated IP(3) 3-kinase isoform A expressed in HeLa cells, COS-7 cells, and primary neuronal cultures, we have defined a novel N-terminal 66-amino acid F-actin-binding region that localizes the kinase to dendritic spines. The region is necessary and sufficient for binding F-actin and consists of a proline-rich stretch followed by a predicted alpha-helix. We also localized endogenous IP(3) 3-kinase A to the dendritic spines of pyramidal neurons in primary hippocampal cultures, where it is co-localized postsynaptically with calcium/calmodulin-dependent protein kinase II. Our experiments suggest a link between inositol phosphate metabolism, calcium signaling, and the actin cytoskeleton in dendritic spines. The phosphorylation of IP(3) in dendritic spines to produce IP(4) is likely to be important for modulating the compartmentalization of calcium at synapses.
Assuntos
Actinas/metabolismo , Neurônios/enzimologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Células COS , Sinalização do Cálcio/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Extratos Celulares , Citoesqueleto/metabolismo , Detergentes/química , Proteínas de Fluorescência Verde , Células HeLa , Hipocampo/enzimologia , Hipocampo/metabolismo , Humanos , Proteínas Luminescentes/metabolismo , Neurônios/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/química , Testes de Precipitina , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Ratos , Sinapses/metabolismo , TransfecçãoRESUMO
Following the discovery of inositol-1,4,5-trisphosphate as a second messenger, many other inositol phosphates were discovered in quick succession, with some understanding of their synthesis pathways and a few guesses at their possible functions. But then it all seemed to go comparatively quiet, with an explosion of interest in the inositol lipids. Now the water-soluble phase is once again becoming a focus of interest. Old and new data point to a new vista of inositol phosphates, with functions in many diverse aspects of cell biology, such as ion-channel physiology, membrane dynamics and nuclear signalling.
Assuntos
Células Eucarióticas/metabolismo , Fosfatos de Inositol/metabolismo , Transdução de Sinais/fisiologia , Água/metabolismo , Animais , HumanosRESUMO
PURPOSE: Farming is associated with exposure to many potential hazards including pesticides and other agents, but the quality of self-reported data on farm exposures has not been well studied. METHODS: The reproducibility of self-reported farming history was evaluated among women in a population-based, case-control study of breast cancer in North Carolina. Thirty cases and 31 controls were randomly re-interviewed by telephone an average of 13.8 months after the initial interview. The initial interview was based on a farm-by-farm questionnaire, while the repeat interview was based on a shorter ever/never questionnaire. Agreement was estimated using proportions in exact agreement, kappa (kappa), and intraclass correlation coefficients (ICC). RESULTS: In general, group prevalences and means were higher on re-interview. Kappa estimates ranged from 0.15 to 0.84 among cases, and 0.26 to 0.87 among controls, with most estimates falling between 0.5 and 0.8. Moderate to almost perfect agreement (kappa) was observed for questions on crop work (0.47-0.70), crop type (0.56-0.82), pesticide application to tobacco (0.77), and farm residence (0.84). ICC estimates for continuous variables showed fair to substantial agreement (0.30 to 0.69 among cases, 0.38 to 0.69 among controls). Older cases, less educated cases, cases who lived on more than one farm, and cases with longer time intervals between interviews gave lower total agreement than similar groups of controls. CONCLUSIONS: Agreement estimates in this study are similar to those for other types of exposure information typically collected in epidemiologic studies. Nevertheless, a farm-by-farm method of exposure assessment may be preferable to an ever/never determination.
Assuntos
Agricultura/estatística & dados numéricos , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/epidemiologia , Exposição Ocupacional/análise , Praguicidas/efeitos adversos , Análise de Variância , Estudos de Casos e Controles , Coleta de Dados/métodos , Feminino , Humanos , Pessoa de Meia-Idade , North Carolina , Exposição Ocupacional/estatística & dados numéricos , Reprodutibilidade dos Testes , População Rural , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: This study investigated the association between physician recommendation for mammography and race/ethnicity, socioeconomic status, and other characteristics in a rural population. METHODS: In 1993 through 1994, we surveyed 1933 Black women and White women 52 years and older in 10 rural counties. RESULTS: Fifty-three percent of the women reported a physician recommendation in the past year. White women reported recommendations significantly more often than did Black women (55% vs 45%; odds ratio = 1.49). Controlling for educational attainment and income eliminated the apparent racial/ethnic difference. After control for 5 personal, 4 health, and 3 access characteristics, recommendation for mammography was found to be more frequent among women who had access to the health care system (i.e., had a regular physician and health insurance). Recommendation was less frequent among women who were vulnerable (i.e., were older, had lower educational attainment, had lower annual family income). CONCLUSIONS: Socioeconomic status, age, and other characteristics--but not race/ethnicity--were related to reports of a physician recommendation, a precursor strongly associated with mammography use. Efforts to increase physician recommendation should include complementary efforts to help women address socioeconomic and other barriers to mammography use.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Mamografia/estatística & dados numéricos , Padrões de Prática Médica , Encaminhamento e Consulta , População Branca/estatística & dados numéricos , Idoso , Estudos de Coortes , Feminino , Acessibilidade aos Serviços de Saúde , Nível de Saúde , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , North Carolina/epidemiologia , Razão de Chances , Serviços de Saúde Rural , Fatores SocioeconômicosRESUMO
Infection remains an important cause of morbidity and mortality after bone marrow or stem cell transplantation. To evaluate the role of obtaining blood cultures for intermittent or persistent fever in neutropenic patients on antibiotic therapy, we performed a retrospective chart review of 196 consecutive patients admitted to the Bone Marrow Transplant Unit at the University of North Carolina Hospitals from 1995 to 1998. From the cohort of 196 patients, 154 patients developed neutropenic fever. The initial blood culture was positive in 16 of 145 patients during the first fever episode giving a prevalence of 11%. From the total of 109 patients that had blood cultures drawn after day 1 of fever, five patients had blood cultures positive for a pathogen, a prevalence of 4.6%. In only one patient, did blood cultures drawn after day 1 identify an organism not present on day 1 (prevalence 0.9%). After reviewing the results in the first 105 patients, we changed our timing of collection of blood cultures. Forty-nine patients were treated in this manner and we found that the mean number of blood cultures decreased from 9.2 to 4.7 per patient without a change in the frequency of infectious complications or length of hospitalization.
Assuntos
Bacteriemia/diagnóstico , Técnicas Bacteriológicas/estatística & dados numéricos , Transplante de Medula Óssea , Neutropenia/microbiologia , Neutropenia/terapia , Adolescente , Adulto , Idoso , Antibacterianos/administração & dosagem , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Técnicas Bacteriológicas/economia , Técnicas Bacteriológicas/métodos , Sangue/microbiologia , Criança , Pré-Escolar , Estudos de Coortes , Meios de Cultura , Feminino , Febre/tratamento farmacológico , Febre/microbiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de TempoRESUMO
HLA-identical bone marrow or stem cell transplantation from a sibling is the preferred treatment for patients with chronic myelogenous leukemia, bone marrow failure syndromes, relapsed acute leukemia, and specific inborn errors of metabolism. Several groups have shown that granulocyte colony-stimulating factor (G-CSF)--mobilized peripheral blood progenitor cells (PBPCs) obtained from HLA-matched siblings are effective in reconstitution of marrow function after marrow ablative conditioning therapy. To evaluate whether G-CSF treatment before bone marrow harvest leads to enhanced recovery of PBPC counts and recovery from limited graft-versus-host disease (GVHD), we assessed the outcome of a sequential cohort of patients treated identically and then given either G-CSF--mobilized PBPCs or G-CSF--stimulated bone marrow from HLA-identical siblings. We show that the time to neutrophil engraftment is identical in the 2 cohorts, whereas platelet engraftment is earlier with the use of PBPCs. The incidence of acute GVHD was decreased, and that of chronic GVHD significantly decreased, in the group receiving bone marrow. Overall survival was not different between the 2 groups. Thus, G-CSF--stimulated bone marrow offers a source of stem cells that allows for early neutrophil engraftment with a decreased risk of GVHD.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Células Sanguíneas , Células da Medula Óssea , Criança , Sobrevivência de Enxerto , Teste de Histocompatibilidade , Humanos , Pessoa de Meia-Idade , Neoplasias/terapia , Análise de Sobrevida , Transplante HomólogoRESUMO
BACKGROUND: A modified Phase I trial was conducted evaluating the incorporation of 3-dimensional conformal radiation therapy (3DCRT) into a strategy of sequential and concurrent carboplatin/paclitaxel in Stage III, unresectable nonsmall cell lung carcinoma (NSCLC). In addition, dose escalation of thoracic conformal radiation therapy (TCRT) from 60 to 74 gray (Gy) was performed. Endpoints included response rate, toxicity, and survival. METHODS: Twenty-nine patients with unresectable Stage III NSCLC were included. Patients received 2 cycles of induction carboplatin (AUC 6) and paclitaxel (225 mg/m(2)/3 hours) every 21 days. On Day 43, concurrent TCRT and weekly (x6) carboplatin (AUC 2) and paclitaxel (45 mg/m(2)/3 hours) was initiated. The TCRT dose was escalated from 60 to 74 Gy in 4 cohorts. RESULTS: The response rate to induction carboplatin/paclitaxel was 52%. Three patients (10%) experienced disease progression during the induction phase. No dose-limiting toxicity was seen during the escalation of the TCRT dose from 60 to 74 Gy. The major toxicity was esophagitis, with 18% of patients developing Radiation Therapy Oncology Group Grade 3 esophagitis. The overall response rate was 70% (1 complete response and 18 partial responses). Survival rates at 1 and 2 years were 69% and 45%, with a median survival of 21 months. The 1-year progression free survival probability was 41% (95% confidence interval, 23-59%). CONCLUSIONS: Incorporation of 3DCRT with sequential and concurrent carboplatin/paclitaxel is feasible, and dose escalation of TCRT to 74 Gy is possible with acceptable toxicity. Overall response and survival rates are encouraging. Accrual is continuing in a Phase II fashion at 74 Gy with sequential and concurrent carboplatin/paclitaxel.