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BACKGROUND: We developed a classifier using RNA sequencing data that identifies the usual interstitial pneumonia (UIP) pattern for the diagnosis of idiopathic pulmonary fibrosis. We addressed significant challenges, including limited sample size, biological and technical sample heterogeneity, and reagent and assay batch effects. RESULTS: We identified inter- and intra-patient heterogeneity, particularly within the non-UIP group. The models classified UIP on transbronchial biopsy samples with a receiver-operating characteristic area under the curve of ~ 0.9 in cross-validation. Using in silico mixed samples in training, we prospectively defined a decision boundary to optimize specificity at ≥85%. The penalized logistic regression model showed greater reproducibility across technical replicates and was chosen as the final model. The final model showed sensitivity of 70% and specificity of 88% in the test set. CONCLUSIONS: We demonstrated that the suggested methodologies appropriately addressed challenges of the sample size, disease heterogeneity and technical batch effects and developed a highly accurate and robust classifier leveraging RNA sequencing for the classification of UIP.
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Pneumonias Intersticiais Idiopáticas/diagnóstico , Pneumonias Intersticiais Idiopáticas/genética , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/genética , Análise de Sequência de RNA/métodos , Área Sob a Curva , Biópsia , Biologia Computacional/métodos , Simulação por Computador , Diagnóstico Diferencial , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Aprendizado de Máquina , Estudos Prospectivos , Curva ROC , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Clinical guidelines specify that diagnosis of interstitial pulmonary fibrosis (IPF) requires identification of usual interstitial pneumonia (UIP) pattern. While UIP can be identified by high resolution CT of the chest, the results are often inconclusive, making surgical lung biopsy necessary to reach a definitive diagnosis (Raghu et al., Am J Respir Crit Care Med 183(6):788-824, 2011). The Envisia genomic classifier differentiates UIP from non-UIP pathology in transbronchial biopsies (TBB), potentially allowing patients to avoid an invasive procedure (Brown et al., Am J Respir Crit Care Med 195:A6792, 2017). To ensure patient safety and efficacy, a laboratory developed test (LDT) must meet strict regulatory requirements for accuracy, reproducibility and robustness. The analytical characteristics of the Envisia test are assessed and reported here. METHODS: The Envisia test utilizes total RNA extracted from TBB samples to perform Next Generation RNA Sequencing. The gene count data from 190 genes are then input to the Envisia genomic classifier, a machine learning algorithm, to output either a UIP or non-UIP classification result. We characterized the stability of RNA in TBBs during collection and shipment, and evaluated input RNA mass and proportions on the limit of detection of UIP. We evaluated potentially interfering substances such as blood and genomic DNA. Intra-run, inter-run, and inter-laboratory reproducibility of test results were also characterized. RESULTS: RNA content within TBBs preserved in RNAprotect is stable for up to 14 days with no detectable change in RNA quality. The Envisia test is tolerant to variation in RNA input (5 to 30 ng), with no impact on classifier results. The Envisia test can tolerate dilution of non-UIP and UIP classification signals at the RNA level by up to 60% and 20%, respectively. Analytical specificity studies utilizing UIP and non-UIP samples mixed with genomic DNA (up to 30% relative input) demonstrated no impact to classifier results. The Envisia test tolerates up to 22% of blood contamination, well beyond the level observed in TBBs. The test is reproducible from RNA extraction through to Envisia test result (standard deviation of 0.20 for Envisia classification scores on > 7-unit scale). CONCLUSIONS: The Envisia test demonstrates the robust analytical performance required of an LDT. Envisia can be used to inform the diagnoses of patients with suspected IPF.
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Perfilação da Expressão Gênica/métodos , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Análise de Sequência de RNA , Algoritmos , Biópsia , Broncoscopia , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Aprendizado de Máquina , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: In the appropriate clinical setting, the diagnosis of idiopathic pulmonary fibrosis (IPF) requires a pattern of usual interstitial pneumonia to be present on high-resolution chest CT (HRCT) or surgical lung biopsy. A molecular usual interstitial pneumonia signature can be identified by a machine learning algorithm in less-invasive transbronchial lung biopsy samples. We report prospective findings for the clinical validity and utility of this molecular test. METHODS: We prospectively recruited 237 patients for this study from those enrolled in the Bronchial Sample Collection for a Novel Genomic Test (BRAVE) study in 29 US and European sites. Patients were undergoing evaluation for interstitial lung disease and had had samples obtained by clinically indicated surgical or transbronchial biopsy or cryobiopsy for pathology. Histopathological diagnoses were made by experienced pathologists. Available HRCT scans were reviewed centrally. Three to five transbronchial lung biopsy samples were collected from all patients specifically for this study, pooled by patient, and extracted for transcriptomic sequencing. After exclusions, diagnostic histopathology and RNA sequence data from 90 patients were used to train a machine learning algorithm (Envisia Genomic Classifier, Veracyte, San Francisco, CA, USA) to identify a usual interstitial pneumonia pattern. The primary study endpoint was validation of the classifier in 49 patients by comparison with diagnostic histopathology. To assess clinical utility, we compared the agreement and confidence level of diagnosis made by central multidisciplinary teams based on anonymised clinical information and radiology results plus either molecular classifier or histopathology results. FINDINGS: The classifier identified usual interstitial pneumonia in transbronchial lung biopsy samples from 49 patients with 88% specificity (95% CI 70-98) and 70% sensitivity (47-87). Among 42 of these patients who had possible or inconsistent usual interstitial pneumonia on HRCT, the classifier showed 81% positive predictive value (95% CI 54-96) for underlying biopsy-proven usual interstitial pneumonia. In the clinical utility analysis, we found 86% agreement (95% CI 78-92) between clinical diagnoses using classifier results and those using histopathology data. Diagnostic confidence was improved by the molecular classifier results compared with histopathology results in 18 with IPF diagnoses (proportion of diagnoses that were confident or provisional with high confidence 89% vs 56%, p=0·0339) and in all 48 patients with non-diagnostic pathology or non-classifiable fibrosis histopathology (63% vs 42%, p=0·0412). INTERPRETATION: The molecular test provided an objective method to aid clinicians and multidisciplinary teams in ascertaining a diagnosis of IPF, particularly for patients without a clear radiological diagnosis, in samples that can be obtained by a less invasive method. Further prospective clinical validation and utility studies are planned. FUNDING: Veracyte.
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Algoritmos , Biópsia/estatística & dados numéricos , Fibrose Pulmonar Idiopática/diagnóstico , Aprendizado de Máquina/estatística & dados numéricos , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Idoso , Biópsia/métodos , Diagnóstico Diferencial , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X/métodosRESUMO
Importance: Use of next-generation sequencing of RNA and machine learning algorithms can classify the risk of malignancy in cytologically indeterminate thyroid nodules to limit unnecessary diagnostic surgery. Objective: To measure the performance of a genomic sequencing classifier for cytologically indeterminate thyroid nodules. Design, Setting, and Participants: A blinded validation study was conducted on a set of cytologically indeterminate thyroid nodules collected by fine-needle aspiration biopsy between June 2009 and December 2010 from 49 academic and community centers in the United States. All patients underwent surgery without genomic information and were assigned a histopathology diagnosis by an expert panel blinded to all genomic information. There were 210 potentially eligible thyroid biopsy samples with Bethesda III or IV indeterminate cytopathology that constituted a cohort previously used to validate the gene expression classifier. Of these, 191 samples (91.0%) had adequate residual RNA for validation of the genomic sequencing classifier. Algorithm development and independent validation occurred between August 2016 and May 2017. Exposures: Thyroid nodule surgical histopathology diagnosis by an expert panel blinded to all genomic data. Main Outcomes and Measures: The primary end point was measurement of genomic sequencing classifier sensitivity, specificity, and negative and positive predictive values in biopsies from Bethesda III and IV nodules. The secondary end point was measurement of classifier performance in biopsies from Bethesda II, V, and VI nodules. Results: Of the 183 included patients, 142 (77.6%) were women, and the mean (range) age was 51.7 (22.0-85.0) years. The genomic sequencing classifier had a sensitivity of 91% (95% CI, 79-98) and a specificity of 68% (95% CI, 60-76). At 24% cancer prevalence, the negative predictive value was 96% (95% CI, 90-99) and the positive predictive value was 47% (95% CI, 36-58). Conclusions and Relevance: The genomic sequencing classifier demonstrates high sensitivity and accuracy for identifying benign nodules. Its 36% increase in specificity compared with the gene expression classifier potentially increases the number of patients with benign nodules who can safely avoid unnecessary diagnostic surgery.
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Algoritmos , Perfilação da Expressão Gênica/métodos , RNA Neoplásico/genética , Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/diagnóstico , Tireoidectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Reprodutibilidade dos Testes , Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/cirurgia , Adulto JovemRESUMO
Seventy-four (74) patients with metastatic melanoma were treated with patient-specific vaccines derived from autologous tumor cell lines. Cryopreserved irradiated tumor cells were injected weekly for 3 weeks, then monthly for 5 months. At a median follow up >6 years, the median event-free survival (EFS) was 4.5 months, with 13 patients alive and progression free 6-12 years later. Median overall survival (OS) was 20.5 months, with 29% 5-year OS. Tumor response rate was 9% among the 35 patients with evaluable disease who received at least 3 injections. Better survival was observed for patients who had minimal rather than clinically evident metastatic disease at the time vaccine therapy was initiated (5-yr OS 47% vs. 13%; p < 0.0001), received granulocyte-macrophage colony-stimulating factor and/or interferon gamma as an adjuvant (5-yr EFS 26% vs. 0%; p < 0.0001) or received an average of <7 million cells for each of the first 3 injections, compared to those who received 7-11.9 million or >12 million cells per injection (5-yr EFS OS 35% vs. 24%; p = 0.041 and p = 0.034). There was a trend toward better EFS for those who had a positive delayed type hypersensitivity (DTH) reaction to an intradermal injection of 1 million irradiated tumor cells at baseline, or converted to positive after 3 injections, compared to those whose DTH remained negative (5-yr EFS 39% vs. 18%; p = 0.159). This treatment approach is feasible, produces minimal toxicity, and is associated with longterm survival in a significant proportion of patients.
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Vacinas Anticâncer/toxicidade , Vacinas Anticâncer/uso terapêutico , Melanoma/imunologia , Linhagem Celular Tumoral , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Humanos , Imunoterapia/métodos , Espectroscopia de Ressonância Magnética , Melanoma/diagnóstico por imagem , Melanoma/mortalidade , Melanoma/patologia , Metástase Neoplásica/imunologia , Seleção de Pacientes , Estudos Retrospectivos , Análise de Sobrevida , Sobreviventes , Tomografia Computadorizada por Raios XRESUMO
RATIONALE: Usual interstitial pneumonia (UIP) is the histopathologic hallmark of idiopathic pulmonary fibrosis. Although UIP can be detected by high-resolution computed tomography of the chest, the results are frequently inconclusive, and pathology from transbronchial biopsy (TBB) has poor sensitivity. Surgical lung biopsy may be necessary for a definitive diagnosis. OBJECTIVES: To develop a genomic classifier in tissue obtained by TBB that distinguishes UIP from non-UIP, trained against central pathology as the reference standard. METHODS: Exome enriched RNA sequencing was performed on 283 TBBs from 84 subjects. Machine learning was used to train an algorithm with high rule-in (specificity) performance using specimens from 53 subjects. Performance was evaluated by cross-validation and on an independent test set of specimens from 31 subjects. We explored the feasibility of a single molecular test per subject by combining multiple TBBs from upper and lower lobes. To address whether classifier accuracy depends upon adequate alveolar sampling, we tested for correlation between classifier accuracy and expression of alveolar-specific genes. RESULTS: The top-performing algorithm distinguishes UIP from non-UIP conditions in single TBB samples with an area under the receiver operator characteristic curve (AUC) of 0.86, with specificity of 86% (confidence interval = 71-95%) and sensitivity of 63% (confidence interval = 51-74%) (31 test subjects). Performance improves to an AUC of 0.92 when three to five TBB samples per subject are combined at the RNA level for testing. Although we observed a wide range of type I and II alveolar-specific gene expression in TBBs, expression of these transcripts did not correlate with classifier accuracy. CONCLUSIONS: We demonstrate proof of principle that genomic analysis and machine learning improves the utility of TBB for the diagnosis of UIP, with greater sensitivity and specificity than pathology in TBB alone. Combining multiple individual subject samples results in increased test accuracy over single sample testing. This approach requires validation in an independent cohort of subjects before application in the clinic.
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Biópsia/métodos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Aprendizado de Máquina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Expressão Gênica , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Análise de Sequência de RNA , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
In patients with metastatic melanoma, sequential single-arm and randomized phase II trials with a therapeutic vaccine consisting of autologous dendritic cells (DCs) loaded with antigens from self-renewing, proliferating, irradiated autologous tumor cells (DC-TC) showed superior survival compared with similar patients immunized with irradiated tumor cells (TC). We wished to determine whether this difference was evident in cohorts who at the time of treatment had (1) no evidence of disease (NED) or (2) had detectable disease. Eligibility criteria and treatment schedules were the same for all three trials. Pooled data confirmed that overall survival (OS) was longer in 72 patients treated with DC-TC compared with 71 patients treated with TC (median OS 60 versus 22 months; 5-year OS 51% versus 32%, p=0.004). Treatment with DC-TC was associated with longer OS in both cohorts. Among 70 patients who were NED at the time that treatment was started, OS was better for DC-TC: 5-year OS 73% versus 43% (p=0.015). Among 73 patients who had detectable metastases, OS was better for DC-TC: median 38.8 months versus 14.7 months, 5-year OS 33% versus 20% (p=0.025). This approach is promising as an adjunct to other therapies in patients who have had metastatic melanoma.
Assuntos
Vacinas Anticâncer/uso terapêutico , Células Dendríticas/transplante , Imunoterapia/métodos , Melanoma/terapia , Células-Tronco Neoplásicas/transplante , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Carga Tumoral , Apresentação de Antígeno , Células Dendríticas/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Interferon gama/administração & dosagem , Masculino , Melanoma/imunologia , Melanoma/secundário , Antígenos Específicos de Melanoma/imunologia , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/imunologia , Neoplasias Cutâneas/imunologia , Taxa de Sobrevida , Células Tumorais Cultivadas/imunologiaRESUMO
Pharmacy logbooks and clinical trial records were used to identify all 60 patients with metastatic melanoma who were treated as inpatients with intermediate-dose, continuous-infusion interleukin-2 (IL-2) in Hoag Hospital during 1987 to 1998. The hospital tumor registry was used to identify contemporary controls who had not received inpatient IL-2, matched for having distant metastatic melanoma, and by year and stage at original diagnosis, gender, and age. The mean time from original diagnosis to the documentation of distant metastatic disease was similar in both groups, 24 to 26 months. From the date of starting IL-2 therapy, patients had a median survival of 8.8 months, 38% 1-year survival, and 20% 5-year survival, with 8 patients alive beyond 5 years. However, there was no difference in survival from the first date of distant metastatic disease (median 25.8 months for IL-2 versus 31.5 months for controls, with survival rates 5 years after metastatic disease of 26% versus 31%). There was also no difference in overall survival from the date of original diagnosis (60.1 months for the IL-2 group versus 86.3 months for controls, with 5-year survival rates of 51% versus 64%, and 10-year survival rates of 29% versus 33%). This single-institution study failed to establish a survival advantage for patients with metastatic melanoma who received intermediate-dose, continuous-infusion IL-2 administered in the inpatient setting, compared to contemporary, matched-control patients who never received inpatient IL-2 therapy. However, the 5-year survival rates after a diagnosis of distant metastatic disease were a surprisingly high 26% to 31% in both groups. In the absence of a control group, the survival impact of IL-2 has probably been overestimated from single-arm phase II and III trials.
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Antineoplásicos/uso terapêutico , Interleucina-2/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Feminino , Humanos , Imunoterapia , Infusões Intravenosas , Interleucina-2/administração & dosagem , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de SobrevidaRESUMO
OBJECTIVE: We established short-term cultures of pure tumor cells for use as autologous tumor cell vaccines in an effort to study the effects of patients-specific immunotherapy. PATIENTS AND METHODS: Surgically resected fresh tumor was obtained from patients with metastatic cancer. Successful tumor cell lines (5 x 10(7)) were expanded to 10(8) cells, irradiated, and cryopreserved for clinical use. Following a baseline test of delayed-type hypersensitivity (DTH) to an i.d. injection of 10(6) irradiated autologous tumor cells, patients received 3 weekly s.c. injections of 10(7) cells, had a repeat DTH test at week-4, then received monthly vaccinations for 5 months. A positive DTH test was defined as > or = 10 mm induration; survival was determined from the first DTH test. RESULTS: Short-term cell lines were successfully established for 299/695 patients (43%). Vaccines were prepared for 231 patients, 142 of whom were treated, and 125 had a baseline DTH test recorded. Median follow up at the time of analysis was greater than 5 years. There was no difference in survival for any of the following: gender, age > 50 years, melanoma histology, anergy to common recall antigens or baseline DTH test result. Only 17 patients had a positive DTH at baseline (14%), but DTH converted from negative to positive in 31/80 (39%) of those who were tested, and in 31/108 (29%) of all patients (intent-to-convert analysis). For the 48 patients who were DTH-positive at entry, or converted to DTH-positive, the median survival was 30.5 months and 5-year survival 41% compared to 11.4 months and 9% 5-year survival for 77 patients whose DTH was never positive (P2 = 0.003). However, survival was even better for patients whose DTH test converted to positive compared to patients who were DTH-positive at baseline (median 37.5 vs 11.9 mos, P2 = 0.066). CONCLUSION: This patient-specific, cell culture-derived, autologous tumor cell vaccine induced anti-tumor immune reactivity that was associated with improved survival in patients with advanced cancer.
Assuntos
Vacinas Anticâncer/uso terapêutico , Hipersensibilidade Tardia/imunologia , Neoplasias/imunologia , Células Tumorais Cultivadas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Neoplasias/terapia , Testes Cutâneos , Taxa de Sobrevida , Resultado do Tratamento , Células Tumorais Cultivadas/efeitos da radiaçãoRESUMO
PURPOSE: The buy-and-bill model of pharmaceuticals has been an economic reality for medical oncology practices for more than 30 years. Infusion services, once just a supportive service, grew exponentially in most practices between 1991 and 2000, to the point at which revenue from these services created a high, which made all things possible, including care of underinsured or uninsured patients. This altered state was further enhanced in the early part of this past decade when the introduction of high-cost chemotherapeutics and biologic agents created the euphoria of big business and a true dollar distortion for even the smallest oncology practice. RESULTS: In 2005, government and payer intervention forced average wholesale price to average sales price conversion to reduce the drug effect. Concurrently, payer scrutiny of utilization and medical necessity with further dose reductions, equating to margins, led many practices to experience painful drug withdrawal symptoms. Despite the enormous financial risk for unreimbursed expense and acknowledged spiraling decline of drug margins of greater than 30% since 2002, the seductive possibility of a financial fix keeps the practices hooked. CONCLUSION: Many practices will make poor financial choices and will gamble with their financial health by consuming precious resources to support the habit. We propose the drug test: Run your practice financials without drugs. Can you cover the total practice expense without drugs? If not, determine your level of dependency on the drug margin, and adjust your service lines and salaries accordingly. We issue the following warning: Drug dependencies may be hazardous to the financial health of your organization.
RESUMO
For more than 20 years interleukin-2 (IL2) was the preferred treatment for medically fit metastatic melanoma patients, but recently two new agents, ipilimumab and vemurafenib, were approved for stage IV disease. Single-institution data were used to determine the long-term survival rate for IL2-treated melanoma patients, and whether use of inpatient IL2 had declined recently. Between May 1987 and April 2010, 150 patients were hospitalized for high-dose, intravenous (i.v.) IL2. The average number of IL2 patients increased from 5.4 per year during 1987-1991 to 5.8 during 1992-1997 after regulatory approval of IL2, to 8.3 during 1998-2006 after a marketing indication in metastatic melanoma was granted, but dropped to 3.0 during 2007-2010. At the time of treatment, median age was 52 years; 27% were 60 years of age or older. At the time of analysis 122 patients were deceased. Median survival from the start date of IL2 treatment was 15.6 months, with a 20% 5-year survival. Among patients enrolled in clinical trials, there were as many nonresponders who survived 5 years as responders, which is consistent with a delayed immunotherapy benefit. In the absence of long-term survival data for these newer agents, IL2 probably should still be the preferred initial treatment for most patients with metastatic melanoma who are medically fit.
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Interleucina-2/administração & dosagem , Melanoma/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Humanos , Interleucina-2/efeitos adversos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Interleukin-2 (IL-2) was the preferred treatment for medically fit patients with advanced kidney cancer, but recently, several targeted therapies have been approved for metastatic renal cell carcinoma. We wished to determine the long-term survival rate for patients with kidney cancer treated with IL-2 and whether the use of intense inpatient IL-2 has declined since the introduction of targeted therapies. Patients who received IL-2 were identified from clinical trial enrollment, pharmacy logs, and financial billing records. Survival was determined from the earliest date of IL-2 therapy. There were 79 patients hospitalized for high-dose infusional IL-2 between March 1989 and March 2009. Median age was 58 years, and 27% were older than 65 years at the time of treatment. At the time of this analysis, 72 patients had deceased. Median survival was 9.9 months, but 5-year survival was 19.4%. The average number of patients with IL-2 increased from 2.2 per year during 1989-1992 to 5.6 during 1993-2001 after FDA approval, but dropped to 2.0 during 2002-2009. High-dose IL-2 is associated with a 5-year survival rate that is higher than objective response rates, suggesting a delayed immunotherapy benefit for some patients. The use of intensive IL-2 has declined dramatically in recent years, but unless a long-term survival benefit can be shown for these new targeted products, we feel that inpatient IL-2 remains the preferred initial treatment.
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Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Sistema de Registros , Estudos Retrospectivos , Resultado do TratamentoRESUMO
UNLABELLED: Between January 2001 and September 2007, we treated 54 metastatic melanoma patients with patient-specific tumor cell vaccines consisting of dendritic cells (DCS), derived from their peripheral blood cells that were cultured in interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor (GM-CSF), which had phagocytosed irradiated autologous tumor cells from a continuously proliferating, self-renewing, autologus tumor cell (TC) culture. The loaded DCs were injected subcutaneously in 500 microg of GM-CSF weekly x three, and then monthly for 5 months, for a total of up to 8 injections. The 34 men and 20 women had a median age of 50.5 years; 32 had M1c (visceral metastases and/or elevated lactate dehydrogenase) as their most advanced disease stage. Overall, 83% had received other systemic therapies, including interferon-alpha (n = 20), biochemotherapy (n = 19), GM-CSF (n = 19), chemotherapy (n = 16), IL-2 (n = 13), and other investigational vaccines (n = 7). Patients received an average of 7.4 vaccinations. Treatment was well-tolerated, with most patients experiencing only mild local pruritus and/or erythema. A positive delayed-type hypersensitivity reaction to purified autologous tumor cells was observed at baseline in only 1 of 54 patients, compared to 12 of 54 following vaccination (p = 0.001). The projected 5-year survival rate is an impressive 54% at a median follow-up of 4.5 years (range, 2.4-7.4) for the 30 surviving patients. This survival was superior to that observed following vaccination with irradiated TC in 48 melanoma patients in a previous trial (64 versus 31 months, p = 0.016). This patient-specific vaccine warrants further investigation, based on its safety and encouraging survival rates. ( CLINICAL TRIAL NUMBER: NCI-V01-1646).
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Antígenos de Neoplasias/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Células Dendríticas/transplante , Melanoma/imunologia , Melanoma/terapia , Adolescente , Adulto , Anticorpos/sangue , Antígenos CD/metabolismo , Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Autoantígenos/uso terapêutico , Biomarcadores Tumorais/sangue , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Citocinas/sangue , Células Dendríticas/metabolismo , Progressão da Doença , Feminino , Gangliosídeos/sangue , Gangliosídeos/imunologia , Humanos , Hipersensibilidade Tardia/imunologia , Interferon gama/sangue , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica/imunologia , Metástase Neoplásica/patologia , Metástase Neoplásica/terapia , Fagocitose/imunologia , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
During 1990-1999, we treated 60 patients with breast cancer who had distant metastases with high-dose chemotherapy and autologous stem cell rescue (HDC) after they had responded to induction chemotherapy. HDC regimens were MiTepa (60 mg/m2 mitoxantrone by continuous intravenous infusion over 3 days plus 300 mg/m2 thiotepa intravenously over 2 hours daily x 3 days) and ICE (12 g/m2 ifosfamide, 1800 mg/m2 carboplatin, 2 g/m2 etoposide; all 3 by continuous intravenous over 4 days). At a median follow up >8 years, the median failure-free survival (FFS) was 13.9 months, median overall survival (OS) 29.1 months, 5-year FFS 12%s and 5-year OS 25%. Thirty-three patients underwent tandem (T) transplants; 27 underwent a single (S) HDC. Median ages for these 2 groups were 45 and 48 years; bone and liver metastases were more prevalent in the T cohort, whereas lung metastases were more prevalent in the S cohort. At a median follow up of 6.5 years for the S group and >9 years for the T group, there were 52 deaths. FFS was better for T: median 15.7 versus 7.7 months (p2 = 0.010) as was OS: median 32.7 versus 17.7 months, 2-year survival 68% versus 41%, and 5-year survival 32% versus 15% (p2 = 0.010). As a group, patients with distant metastatic breast cancer who underwent tandem transplants had a better posttransplant survival than patients who underwent a single HDC.