RESUMEN
OBJECTIVE: Lung cancer is the leading cause of cancer-related death worldwide, and most patients are diagnosed of advanced disease. Molecular-targeted therapy and immunotherapy increase survival among these patients. In this study, we compared the cost of the best treatments available with the amount reimbursed by the Brazilian public healthcare system (Sistema Único de Saúde [SUS]) to treat advanced lung cancer. METHODS: The authors divided lung cancer into 10 subtypes according to histology and molecular profile. A panel of experts defined the best treatment sequencing for each subtype. The authors considered only drug costs retrieved from the Brazilian Health Regulatory Agency official data. The progression-free survival of each regimen was considered as treatment duration. The cost estimate included all postprogression therapies weighted by each subtype proportional frequency. The amount reimbursed by SUS was the sum of the monthly budget accumulated during the estimated treatment duration and then for the proportional frequency of each subtype. RESULTS: The budget reimbursed by SUS for treating each advanced lung cancer case in Brazil is R$8000.00 in average whereas the cost estimate for the best treatment available is R$729 454.00 per case, which represents a difference of 9118%. The budget impact to ensure the reimbursement needed to acquire the best treatments available was estimated in near R$13 billion annually. CONCLUSIONS: The cost estimate of the best treatment available for advanced lung cancer in Brazil is much higher than the amount reimbursed by SUS. This budgetary gap leads to a major access barrier that may compromise the survival outcomes of SUS users.
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Neoplasias Pulmonares , Humanos , Brasil , Neoplasias Pulmonares/terapia , Hospitalización , Costos de los Medicamentos , PresupuestosRESUMEN
The development of therapies that restore or activate the host immune response - the socalled "immuno-oncologic" therapy - has improved the survival of some cancer patients harboring specific tumor types. These drugs, however, are very expensive which has greatly limited their use and consequently reduced the number of patients who could likely benefit. Not to mention, the proportion of patients who display a clinical benefit from therapy is limited. Thus, from a clinical and health economics perspective, there is a pressing need to identify and treat those patients for whom a given immuno- oncologic therapy is most likely to be beneficial. At this end, the identification, validation and use of biomarkers emerge as an important therapeutic tool. Here, we briefly review the state of immunologic biomarker development and utilization and make suggestions for interested clinicians, health policy makers and other stakeholders to prepare for the broader use of biomarkers associated with immuno-oncologic therapy in routine practice. The biomarker field is clearly in its earliest stages and there is no doubt that continued research will identify new biomarkers with valuable clinical indications. Of course, the clinical utility of a biomarker must consider patient preferences and perspectives. In addition, health economic analyses are crucial to better define the value of immunotherapy based on precision medicine strategies and promote value-based pricing.
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Antineoplásicos Inmunológicos/farmacología , Biomarcadores de Tumor/análisis , Neoplasias/tratamiento farmacológico , Selección de Paciente , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/inmunología , Humanos , Neoplasias/genética , Neoplasias/inmunología , Medicina de Precisión/métodos , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Oral mucositis is an acute toxicity that occurs in patients submitted to chemoradiotherapy to treat head and neck squamous cell carcinoma. In this study, we evaluated differences in gene expression in the keratinocytes of the oral mucosa of patients treated with photobiomodulation therapy and tried to associate the molecular mechanisms with clinical findings. From June 2009 to December 2010, 27 patients were included in a randomized double-blind pilot study. Buccal smears from 13 patients were obtained at days 1 and 10 of chemoradiotherapy, and overall gene expression of samples from both dates were analyzed by complementary DNA (cDNA) microarray. In addition, samples from other 14 patients were also collected at D1 and D10 of chemoradiotherapy for subsequent validation of cDNA microarray findings by qPCR. The expression array analysis identified 105 upregulated and 60 downregulated genes in our post-treatment samples when compared with controls. Among the upregulated genes with the highest fold change, it was interesting to observe the presence of genes related to keratinocyte differentiation. Among downregulated genes were observed genes related to cytotoxicity and immune response. The results indicate that genes known to be induced during differentiation of human epidermal keratinocytes were upregulated while genes associated with cytotoxicity and immune response were downregulated in the laser group. These results support previous clinical findings indicating that the lower incidence of oral mucositis associated with photobiomodulation therapy might be correlated to the activation of genes involved in keratinocyte differentiation.
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Quimioradioterapia , ADN Complementario/genética , Queratinocitos/metabolismo , Terapia por Luz de Baja Intensidad , Análisis por Micromatrices/métodos , Mucosa Bucal/efectos de la radiación , Método Doble Ciego , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estomatitis/etiología , Estomatitis/genéticaRESUMEN
BACKGROUND: Limbic encephalitis was originally described as a rare clinical neuropathological entity involving seizures and neuropsychological disturbances. In this report, we describe cerebral patterns visualized by positron emission tomography in a patient with limbic encephalitis and cholangiocarcinoma. To our knowledge, there is no other description in the literature of cerebral positron emission tomography findings in the setting of limbic encephalitis and subsequent diagnosis of cholangiocarcinoma. CASE PRESENTATION: We describe a case of a 77-year-old Caucasian man who exhibited persistent cognitive changes 2 years before his death. A cerebral scan obtained at that time by 2-deoxy-2-[fluorine-18]fluoro- D -glucose integrated with computed tomography-positron emission tomography showed low radiotracer uptake in the frontal and temporal lobes. Cerebrospinal fluid analysis indicated the presence of voltage-gated potassium channel antibodies. Three months before the patient's death, a lymph node biopsy indicated a cholangiocarcinoma, and a new cerebral scan obtained by 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography-positron emission tomography showed an increment in the severity of metabolic deficit in the frontal and parietal lobes, as well as hypometabolism involving the temporal lobes. Two months before the patient's death, cerebral metastases were detected on a contrast-enhanced computed tomographic scan. Postmortem examination revealed a cholangiocarcinoma with multiple metastases including the lungs and lymph nodes. The patient's brain weighed 1300 g, and mild cortical atrophy, ex vacuo dilation of the ventricles, and mild focal thickening of the cerebellar leptomeninges, which were infiltrated by neoplastic epithelial cells, were observed. CONCLUSIONS: These findings support the need for continued vigilance in malignancy surveillance in patients with limbic encephalitis and early cerebral positron emission tomographic scan abnormalities. The difficulty in early diagnosis of small tumors, such as a cholangiocarcinoma, is discussed in the context of the clinical utility of early cerebral hypometabolism detected by 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography-positron emission tomography in patients with rapidly progressive dementia.
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Neoplasias de los Conductos Biliares/complicaciones , Encefalopatías/complicaciones , Encefalopatías/diagnóstico por imagen , Colangiocarcinoma/complicaciones , Fluorodesoxiglucosa F18 , Encefalitis Límbica/complicaciones , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Resultado Fatal , Humanos , Masculino , RadiofármacosRESUMEN
BACKGROUND: Oral mucositis is a major event increasing treatment costs of head and neck squamous cell carcinoma (HNSCC) patients treated with chemoradiation (CRT). This study was designed to estimate the cost-effectiveness of low-level laser therapy (LLLT) to prevent oral mucositis in HNSCC patients receiving CRT. METHODS: From June 2007 to December 2010, 94 patients with HNSCC of nasopharynx, oropharynx, and hypopharynx entered a prospective, randomized, double blind, placebo-controlled, phase III trial. CRT consisted of conventional radiotherapy (RT: 70.2 Gy, 1.8 Gy/d, 5 times/wk)+concurrent cisplatin (100mg/m2) every 3 weeks. An InGaAlP (660 nm-100 mW-4J/cm2) laser diode was used for LLLT. RESULTS: From the perspective of Brazil's public health care system (SUS), total costs were higher in Placebo Group (PG) than Laser Group (LG) for opioid use (LG=US$ 9.08, PG=US$ 44.28), gastrostomy feeding (LG=US$ 50.50, PG=US$ 129.86), and hospitalization (PG=US$ 77.03). In LG, the cost was higher for laser therapy only (US$ 1880.57). The total incremental cost associated with the use of LLLT was US$ 1689.00 per patient. The incremental cost-effectiveness ratio (ICER) was US$ 4961.37 per grade 3-4 OM case prevented compared to no treatment. CONCLUSIONS: Our results indicate that morbidity was lower in the Laser Group and that LLLT was more cost-effective than placebo up to a threshold of at least US$ 5000 per mucositis case prevented. CLINICAL TRIAL INFORMATION: NCT01439724.
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Carcinoma de Células Escamosas/terapia , Quimioradioterapia/efectos adversos , Análisis Costo-Beneficio , Neoplasias de Cabeza y Cuello/terapia , Terapia por Luz de Baja Intensidad/economía , Mucositis/prevención & control , Anciano , Brasil , Carcinoma de Células Escamosas/economía , Quimioradioterapia/economía , Método Doble Ciego , Femenino , Neoplasias de Cabeza y Cuello/economía , Humanos , Masculino , Persona de Mediana Edad , Mucositis/economía , Estudios Prospectivos , Resultado del TratamientoRESUMEN
The advent and improvement of high-throughput sequencing over the past decade leveraged the study of whole genomes and transcriptomes of different organisms at lower costs. In transcriptomics, RNA-Seq expands our capacity to understand gene expression in different tissues and pathologies, and how alternative splicing might affect the final protein sequence. Here, we discuss the association of using transcriptome and proteome high-throughput data to foster drug discovery. Using this innovative strategy, some research groups have already identified computationally predicted novel peptides derived from putative splice variants in experimental human proteome data. These discoveries provide new opportunities for targeted drug development.
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Empalme Alternativo , Descubrimiento de Drogas , Proteoma , Animales , Bases de Datos Genéticas , HumanosRESUMEN
BACKGROUND: Cisplatin-based chemoradiation (CRT) is the standard treatment for patients with locally advanced cervical cancer. Epidermal growth factor receptor (EGFR) is frequently overexpressed in cervical cancer, and EGFR inhibition itself has antitumor effects and potentiates CRT. Results of a previous phase 1 trial of the EGFR inhibitor erlotinib combined with cisplatin-based CRT (E + CRT) recommended a phase 2 erlotinib dose of 150 mg/day. METHODS: Eligibility criteria included International Federation of Gynecology and Obstetrics stage IIB to IIIB epidermoid cervical cancer, no prior therapy, and an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients received erlotinib at a dose of 150 mg/day 1 week before and in combination with cisplatin (40 mg/m(2) administered weekly for 5 cycles) and radiotherapy (4500 centigrays in 25 fractions), followed by brachytherapy (4 fractions at a dose of 600 centigrays weekly). RESULTS: A total of 36 patients completed treatment with E + CRT. The median duration of therapy was 77 days and the median follow-up period was 59.3 months. The therapy was well tolerated overall, and 34 patients (94.4%) achieved a complete response. The 2-year and 3-year cumulative overall and progression-free survival rates were 91.7% and 80.6% and 80% and 73.8%, respectively. CONCLUSIONS: Treatment with E + CRT appears to be safe and exerts significant activity against locally advanced cervical cancer. To the best of the authors' knowledge, this is the first study to date to demonstrate that a target agent has promising activity against locally advanced cervical cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia , Receptores ErbB/antagonistas & inhibidores , Neoplasias del Cuello Uterino/terapia , Adulto , Anciano , Braquiterapia , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Clorhidrato de Erlotinib , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patologíaRESUMEN
The adolescent and young adult (AYA) is defined as a patient of 15 to 39 years of age at initial cancer diagnosis, and this group has particular medical needs and age-related issues. Excluding violent deaths, cancer is the leading cause of death among the AYA population. Lymphomas, melanoma, testicular cancer, female genital tract malignancies, thyroid cancer, bone and soft tissue sarcomas, leukemias, central nervous system tumors, breast cancer, and nongonadal germ cell tumors account for 95 % of the cancers in this group. Among those, the epithelial cancer of AYA comprehends the minimum amount and its incidence rates tend to increase with age. This review presents information about epidemiology, biologic peculiarities, as well as standard treatment strategies for epithelial cancers in AYA.
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Neoplasias Glandulares y Epiteliales , Adolescente , Adulto , Humanos , Neoplasias Glandulares y Epiteliales/epidemiología , Neoplasias Glandulares y Epiteliales/terapia , Adulto JovenAsunto(s)
Adenocarcinoma/patología , Neoplasias Encefálicas/tratamiento farmacológico , ADN de Neoplasias/genética , Receptores ErbB/genética , Neoplasias Pulmonares/patología , Mutación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma del Pulmón , Anciano , Biopsia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundario , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib , Exones , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos XRESUMEN
Intron splicing is one of the most important steps involved in the maturation process of a pre-mRNA. Although the sequence profiles around the splice sites have been studied extensively, the levels of sequence identity between the exonic sequences preceding the donor sites and the intronic sequences preceding the acceptor sites has not been examined as thoroughly. In this study we investigated identity patterns between the last 15 nucleotides of the exonic sequence preceding the 5' splice site and the intronic sequence preceding the 3' splice site in a set of human protein-coding genes that do not exhibit intron retention. We found that almost 60% of consecutive exons and introns in human protein-coding genes share at least two identical nucleotides at their 3' ends and, on average, the sequence identity length is 2.47 nucleotides. Based on our findings we conclude that the 3' ends of exons and introns tend to have longer identical sequences within a gene than when being taken from different genes. Our results hold even if the pairs are non-consecutive in the transcription order.
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Exones/genética , Intrones/genética , Secuencia de Bases , Humanos , Proteínas/genéticaRESUMEN
Some proteins, canonically not associated with amyloid diseases, can aggregate into amyloid-like fibrils under special conditions. Our group hypothesized that stressful cancer microenvironment might induce the formation of insoluble deposits of p53 mutant protein. A cohort of 28 non-small cell lung cancer (NSCLC) patients was used to test the aforementioned hypothesis. Tumor specimens were assessed for TP53 mutations using DNA sequencing and for amyloid formation by Congo red staining. TP53 mutations were present in 57% of patients, whereas no amyloid deposits were detected in tissue sections under polarized light microscopy. Mutant p53 proteins are not associated with the appearance of amyloid-like fibrils in NSCLC samples, and DNA sequencing remains the standard method to detect such abnormality.
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Amiloide/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Proteínas Mutantes/genética , Mutación/genética , Proteína p53 Supresora de Tumor/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , ADN de Neoplasias/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , PronósticoRESUMEN
BACKGROUND: Clinical studies have shown antineoplastic effectiveness of monoclonal antibodies (MAbs) against EGFR for different indications. Several MAbs directed to EGFR were developed recently, such as matuzumab, but there is still lack of information on preclinical data on its combination with chemo-radiation. Thus, the present study intended to examine the molecular pathways triggered by matuzumab alone or associated to chemo-radiotherapy in gynecological cell lines and its impact on cell growth and signaling. RESULTS: Combination of matuzumab with radiation and cisplatin did not enhance its cytostatic effects on A431, Caski and C33A cells (high, intermediate and low EGFR expression, respectively) in clonogenic assays, when compared to controls. The lack of effect was mediated by persistent signaling through EGFR due to its impaired degradation. In spite of the fact that matuzumab inhibited phosphorylation of EGFR, it had no effect upon cell viability. To analyze which downstream molecules would be involved in the EGFR signaling in the presence of matuzumab, we have tested it in combination with either PD98059 (MAPK inhibitor), or LY294002 (PI3K inhibitor). Matuzumab exhibited a synergic effect with LY294002, leading to a reduction of Akt phosphorylation that was followed by a decrease in A431 and Caski cells survival. The combination of PD98059 and matuzumab did not show the same effect suggesting that PI3K is an important effector of EGFR signaling in matuzumab-treated cells. Nonetheless, matuzumab induced ADCC in Caski cells, but not in the C33A cell line, suggesting that its potential therapeutic effects in vitro are indeed dependent on EGFR expression. CONCLUSIONS: Matuzumab combined with chemoradiation did not induce cytotoxic effects on gynecological cancer cell lines in vitro, most likely due to impaired EGFR degradation. However, a combination of matuzumab and PI3K inhibitor synergistically inhibited pAkt and cell survival, suggesting that the use of PI3K/Akt inhibitors could overcome intrinsic resistance to matuzumab in vitro. Altogether, data presented here can pave the way to a rational design of clinical strategies in patients with resistant profile to anti-EGFR inhibitors based on combination therapy.
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Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Regulación hacia Abajo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
PURPOSE: Erlotinib, an oral tyrosine kinase inhibitor, is active against head-and-neck squamous cell carcinoma (HNSCC) and possibly has a synergistic interaction with chemotherapy and radiotherapy. We investigated the safety and efficacy of erlotinib added to cisplatin and radiotherapy in locally advanced HNSCC. METHODS AND MATERIALS: In this Phase I/II trial 100 mg/m(2) of cisplatin was administered on Days 8, 29, and 50, and radiotherapy at 70 Gy was started on Day 8. During Phase I, the erlotinib dose was escalated (50 mg, 100 mg, and 150 mg) in consecutive cohorts of 3 patients, starting on Day 1 and continuing during radiotherapy. Dose-limiting toxicity was defined as any Grade 4 event requiring radiotherapy interruptions. Phase II was initiated 8 weeks after the last Phase I enrollment. RESULTS: The study accrued 9 patients in Phase I and 28 in Phase II; all were evaluable for efficacy and safety. No dose-limiting toxicity occurred in Phase I, and the recommended Phase II dose was 150 mg. The most frequent nonhematologic toxicities were nausea/vomiting, dysphagia, stomatitis, xerostomia and in-field dermatitis, acneiform rash, and diarrhea. Of the 31 patients receiving a 150-mg daily dose of erlotinib, 23 (74%; 95% confidence interval, 56.8%-86.3%) had a complete response, 3 were disease free after salvage surgery, 4 had inoperable residual disease, and 1 died of sepsis during treatment. With a median 37 months' follow-up, the 3-year progression-free and overall survival rates were 61% and 72%, respectively. CONCLUSIONS: This combination appears safe, has encouraging activity, and deserves further studies in locally advanced HNSCC.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Brasil , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Intervalos de Confianza , Esquema de Medicación , Erupciones por Medicamentos/etiología , Clorhidrato de Erlotinib , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Neoplasias Hipofaríngeas/tratamiento farmacológico , Neoplasias Hipofaríngeas/mortalidad , Neoplasias Hipofaríngeas/patología , Neoplasias Hipofaríngeas/radioterapia , Neoplasias Laríngeas/tratamiento farmacológico , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/patología , Neoplasias Laríngeas/radioterapia , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/tratamiento farmacológico , Neoplasias Orofaríngeas/mortalidad , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/radioterapia , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Dosificación Radioterapéutica , Terapia Recuperativa/métodos , Tasa de SupervivenciaRESUMEN
PURPOSE: The aim of this study was to investigate whether mRNA expression of the apoptosis-associated genes, XAF1 and XIAP, in bladder cancer patients correlates with response to neoadjuvant treatment. METHODS: Gene expression was analyzed by a real-time quantitative PCR method in paired samples from 14 bladder cancer patients treated with a combination of neoadjuvant gemcitabine and cisplatin. The prognostic significance of XAF1 and XIAP mRNA expression as well as the correlation with several clinical and pathological findings were evaluated. RESULTS: The clinical response in the XAF1-high subset (n = 5) was remarkably higher compared with the XAF1-low subset (n = 9) (100% vs. 44.4%; P = 0.038). These results translated into a notably improvement of progression-free survival (PFS) in the XAF1-high subset (log-rank P = 0.012). In addition, patients in the XAF1-high subset had a 3.9-fold decreased chance of dying from the disease (hazard ratio for death (HR), 0.257; (CI 95%), 0.043-1.536, P = 0.036). When we evaluated the expression of XIAP, although an inverse correlation was found between expression and pathological response, there were no statistically significant associations with the clinical response, the length of PFS, and OS. CONCLUSIONS: This is one of the few studies to address the role of XAF1 in a clinical setting. The data presented here identify XAF1 as a novel predictive and prognostic factor in bladder cancer patients. Furthermore, our observations are in line with previous studies, which point towards XAF1 as a tumor-suppressor gene. Nonetheless, additional studies, both mechanistic and translational, are warranted and may help not only in corroborating the role of XAF1 as a prognostic marker, but also as a potential target for anticancer therapy.
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Quimioterapia Adyuvante/métodos , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/fisiología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/cirugía , Proteínas Adaptadoras Transductoras de Señales , Anciano , Antineoplásicos/uso terapéutico , Proteínas Reguladoras de la Apoptosis , Cisplatino/farmacología , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Supervivencia sin Enfermedad , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Pronóstico , Resultado del Tratamiento , GemcitabinaRESUMEN
HYPOTHESIS: The combination of chemotherapy and radiotherapy is a standard nonsurgical treatment for locally advanced laryngeal cancer. Nevertheless, there are no validated markers to predict the outcome of nonsurgical therapies. The impact of previous tracheotomy is not clear in patients submitted to concomitant chemoradiotherapy. STUDY DESIGN: A non-randomized prospective study. Prognostic factors such as stage, age, performance status, number of chemotherapy cycles, radiotherapy dose, stage VIb disease, and previous tracheotomy were analyzed using the Cox's proportional hazard model. The Kaplan-Meier and log rank tests were used to evaluate the progression-free and overall survival. PATIENTS AND METHODS: Patients with stage III/IV laryngeal carcinoma were prospectively selected. Treatment consisted of cisplatin 100 mg/m(2) every 3 weeks for 3 cycles, radiotherapy to a total dose of 70.2 Gy and salvage surgery. RESULTS: Forty-nine patients were analyzed; tracheotomy was performed in 12 patients (24.5%) before therapy. Patients who had previous tracheotomy had a lower rate of complete response (41.7 vs. 75%, p = 0.034, HR 0.55, CI 95% 0.27-1.11), shorter progression free-survival (HR 2.83, CI 95% 1.60-4.88, p < 0.001), and median overall survival (12 vs. 56 months, HR 2.37, CI 95% 1.43-3.93, p < 0.001), in comparison to those without a tracheotomy. Moreover a significant difference was observed in 3-year survival rates (6 vs. 61%, p = 0.001), in favor of the group without tracheotomy. Interestingly, the impact of previous tracheotomy was not altered when adjusted by other prognostic factors (HR 8.7, CI 95% 3.1-24.0, p < 0.001). CONCLUSIONS: Previous tracheotomy is a negative prognostic factor for patients submitted to chemotherapy combined with radiotherapy and should be considered as a negative clinical prognostic factor in the selection of patients for more aggressive treatment strategies.
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Obstrucción de las Vías Aéreas/cirugía , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/terapia , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/terapia , Traqueotomía/métodos , Adulto , Anciano , Obstrucción de las Vías Aéreas/mortalidad , Obstrucción de las Vías Aéreas/patología , Análisis de Varianza , Carcinoma de Células Escamosas/patología , Quimioterapia Adyuvante , Terapia Combinada , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Laríngeas/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Probabilidad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Radioterapia Adyuvante , Medición de Riesgo , Análisis de Supervivencia , Traqueotomía/efectos adversosRESUMEN
PURPOSE: This phase I trial was aimed to determine the maximum tolerated dose and related toxicity of erlotinib (E) when administered concurrently with standard chemoradiation (CRT) for cervical cancer. EXPERIMENTAL DESIGN: In a modified Fibonacci design, the study aimed to study three cohorts of at least three patients receiving escalating doses of erlotinib (50/100/150 mg) combined with cisplatin (40 mg/m(2), weekly, 5 cycles) and radiotherapy (external beam 4,500 cGy in 25 fractions, followed by 4 fractions/600 cGy/weekly of brachytherapy) in squamous cell cervical carcinoma patients, stage IIB to IIIB. RESULTS: Fifteen patients were enrolled, 3 at dose level (DL) 50 mg, 4 at DL 100 mg, and 8 at DL 150 mg. Patients presented median age 47 (36-59), stage IIB (46.2%) and IIIB (53.8%). Overall, E+CRT was well-tolerated. Three patients did not complete the planned schedule. One patient at DL 100 mg withdrew informed consent due to grade 2 rash; at DL 150 mg, 1 patient presented Raynaud's Syndrome and had C interrupted, and another patient presented grade 4 hepatotoxicity. The latter was interpreted as dose limiting toxicity and a new cohort of 150 mg was started. No further grade 4 toxicity occurred. Grade 3 toxicity occurred in 6 cases: diarrhea in 3 patients, rash in 2 patients, and leukopenia in 1 patient. E+CRT did not lead to limiting in-field toxicity. CONCLUSIONS: E+CRT is feasible to locally advanced squamous cell cervical cancer and is well tolerated. The maximum tolerated dose has been defined as 150 mg. To the best of our knowledge, this is the first report of a combination of erlotinib, cisplatin, and pelvic radiotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Cisplatino/administración & dosificación , Quinazolinas/administración & dosificación , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Adulto , Braquiterapia/métodos , Estudios de Cohortes , Terapia Combinada/métodos , Clorhidrato de Erlotinib , Femenino , Humanos , Persona de Mediana Edad , Oncología por Radiación/métodos , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Quimioterapia Adyuvante , Carcinoma de Células Transicionales/cirugía , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Estudios de Seguimiento , Estudios Prospectivos , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
OBJECTIVES: Gemcitabine and cisplatin (GC) is an active combination in the treatment of metastatic bladder cancer. We have prospectively analyzed the efficacy and tolerability of GC as neoadjuvant treatment of invasive bladder cancer. MATERIALS AND METHODS: In this single-institution phase II trial, patients with muscle-invasive transitional cell carcinoma received three cycles of gemcitabine 1200 mg/m2 on days 1 and 8 with cisplatin 75 mg/m2 on day 1 prior to surgery. Radiologic response was evaluated by computed tomography and magnetic resonance imaging. All patients were referred to surgery after chemotherapy completion. RESULTS: Between June 2002 and March 2005, 22 patients (19 males) were enrolled. Median age was 63 years. Initial stage was II (T2) in 11 and III (T3-4) in 11 patients. Median follow-up is 26 months (4-43). Partial or complete radiologic response rate was documented in 13 out of 20 assessable patients (70%). One patient was excluded due to sarcomatoid carcinoma at definitive pathologic examination. Cystectomy was performed in 15 patients and pelvic radiotherapy in four patients. Nine out of 21 patients (43%) relapsed and four (19%) died due to disease progression. Complete pathologic response was observed in four patients (26.7% of 15). Median progression-free survival was 27 months (CI 95% not reached) with median overall survival of 36 months (CI 95%: 28.7 - 43.3). Grade III/IV toxicity was infrequent, with no deaths due to chemotherapy. CONCLUSIONS: The combination of GC is effective and well-tolerated when used as neoadjuvant therapy in muscle-invasive bladder cancer. Longer follow-up is necessary to evaluate its impact on the overall survival of these patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Adolescente , Adulto , Anciano , Carcinoma de Células Transicionales/cirugía , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/cirugía , GemcitabinaRESUMEN
OBJECTIVES: Gemcitabine and cisplatin (GC) is an active combination in the treatment of metastatic bladder cancer. We have prospectively analyzed the efficacy and tolerability of GC as neoadjuvant treatment of invasive bladder cancer MATERIALS AND METHODS: In this single-institution phase II trial, patients with muscle-invasive transitional cell carcinoma received three cycles of gemcitabine 1200 mg/m² on days 1 and 8 with cisplatin 75 mg/m² on day 1 prior to surgery. Radiologic response was evaluated by computed tomography and magnetic resonance imaging. All patients were referred to surgery after chemotherapy completion RESULTS: Between June 2002 and March 2005, 22 patients (19 males) were enrolled. Median age was 63 years. Initial stage was II (T2) in 11 and III (T3-4) in 11 patients. Median follow-up is 26 months (4-43). Partial or complete radiologic response rate was documented in 13 out of 20 assessable patients (70 percent). One patient was excluded due to sarcomatoid carcinoma at definitive pathologic examination. Cystectomy was performed in 15 patients and pelvic radiotherapy in four patients. Nine out of 21 patients (43 percent) relapsed and four (19 percent) died due to disease progression. Complete pathologic response was observed in four patients (26.7 percent of 15). Median progression-free survival was 27 months (CI 95 percent not reached) with median overall survival of 36 months (CI 95 percent: 28.7 - 43.3). Grade III/IV toxicity was infrequent, with no deaths due to chemotherapy CONCLUSIONS: The combination of GC is effective and well-tolerated when used as neoadjuvant therapy in muscle-invasive bladder cancer. Longer follow-up is necessary to evaluate its impact on the overall survival of these patients.