RESUMO
The main purpose of this study was to explore the changes of biomarkers in different developmental stages of bleomycin-induced pulmonary fibrosis (PF) in rats via comprehensive pathophysiology, UPLC-QTOF/MS metabonomic technology, and 16S rRNA gene sequencing of intestinal microbiota. The rats were randomly divided into normal control and 1-, 2- and 4-week model group. The rat model of PF was established by one-time intratracheal instillation of bleomycin. The levels of inflammatory and fibrosis-related factors such as hydroxyproline (HYP), type III procollagen (COL-III), type IV collagen (COL-IV), hyaluronidase (HA), laminin (LN), interleukin (IL)-1ß, IL-6, malondialdehyde (MDA) increased and superoxide dismutase (SOD) decreased as the PF cycle progressed. In the 1-, 2- and 4-week model group, 2, 19 and 18 potential metabolic biomarkers and 3, 16 and 12 potential microbial biomarkers were detected, respectively, which were significantly correlated. Glycerophospholipid metabolism pathway was observed to be an important pathway affecting PF at 1, 2 and 4 weeks; arginine and proline metabolism pathways significantly affected PF at 2 weeks. Linoleic acid metabolism pathway exhibited clear metabolic abnormalities at 2 and 4 weeks of PF, and alpha-linolenic acid metabolism pathway significantly affected PF at 4 weeks.
In this study, metabolomics technology and intestinal microbiota 16S rRNA gene sequencing were used to search for biomarkers with significant differences in each stage of pulmonary fibrosis. Finally, the variation characteristics of each stage of the disease were discussed. The hope is to provide new insights into the development of diagnostic biomarkers and potential therapeutic targets at all stages.
Assuntos
Microbioma Gastrointestinal , Fibrose Pulmonar , Ratos , Animais , Fibrose Pulmonar/induzido quimicamente , RNA Ribossômico 16S , Bleomicina/efeitos adversos , BiomarcadoresRESUMO
PURPOSE: To retrospectively evaluate sclerotherapy using consecutive polidocanol and bleomycin foam (CPBF) for large untreated venous malformations (VMs) and/or those resistant to prior treatment. MATERIALS AND METHODS: This retrospective study included all patients treated with CPBF for untreated VMs larger than 10 mL and/or refractory to treatment between May 2016 and October 2019. Baseline and follow-up VM volumes were measured on fat-suppressed T2-weighted magnetic resonance (MR) imaging. Outcome was evaluated on postprocedural MR imaging volumetry and by a retrospective survey assessing clinical response and adverse events. Imaging response was considered good for volume reduction from 50% to 70% and excellent for volume reduction ≥70%. Symptoms and quality-of-life (QoL) scores were compared before and after CPBF sclerotherapy. RESULTS: Forty-five patients (mean age, 16 years; range, 1-63 years; 25 males) with 57 VMs were analyzed and treated by 80 sclerotherapy. Sixty percent (27 of 45) of patients had undergone prior treatment for VM. Median VM volume was 36.7 mL (interquartile range, 84 mL) on pretherapy MR imaging. Good and excellent results after the last sclerotherapy were achieved in 36% (16 of 45) and 29% (13 of 45) of patients, respectively, corresponding to a decrease of >50% in 60% (34 of 57) of VMs. QoL score increased by at least 3 points, regardless of initial symptoms. Most patients did not desire additional sclerotherapy owing to near complete symptomatic relief, even for patients who did not achieve a good response. Swelling, pain, and motor impairment scores significantly improved after CPBF. Adverse events included fever (44%, 15 of 34) and nausea/vomiting (29%, 10 of 34). CONCLUSIONS: CPBF sclerotherapy represents an effective therapy for large and/or refractory VMs with minimal adverse events.
Assuntos
Escleroterapia , Malformações Vasculares , Masculino , Humanos , Adolescente , Escleroterapia/efeitos adversos , Escleroterapia/métodos , Polidocanol , Estudos Retrospectivos , Soluções Esclerosantes , Bleomicina/efeitos adversos , Qualidade de Vida , Veias/anormalidades , Imageamento por Ressonância Magnética , Malformações Vasculares/diagnóstico por imagem , Malformações Vasculares/terapia , Resultado do TratamentoRESUMO
BACKGROUND: A 2010 study on the impact of cancer mortality on productivity costs found Hodgkin lymphoma to have the second largest productivity cost lost per death in the United States. The ECHELON-1 trial demonstrated that frontline brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) improves overall survival (OS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in stage III/IV classical Hodgkin lymphoma (cHL), reducing the risk of death to 41% (hazard ratio = 0.59; 95% CI = 0.40-0.88; P = 0.009). OBJECTIVES: To assess the estimated impact of frontline treatment choice on mortality and productivity using an oncology simulation model informed by ECHELON-1 data. METHODS: Individual productivity was estimated using the human capital approach and reported via present value lifetime earnings (PVLE) estimates. Deaths avoided and lifeyears saved without and with A+AVD were calculated using a model informed by realworld treatment use, treatment-specific OS, and expert clinicians' opinions. A+AVD use in the base case was 27% (range: 0%-80%). Stage III/IV cHL prevalence over a 10-year period was estimated; downstream lifetime productivity costs were projected without and with A+AVD. RESULTS: In 2031, 3,645 patients were estimated to be newly diagnosed with stage III/IV cHL. Over 10 years with 27% A+AVD vs no A+AVD use, estimates predicted 14% fewer deaths (2,290 vs 2,650) and 14% less total PVLE losses ($1.438 vs $1.664 billion). Results from scenario analyses (40%-80% vs no A+AVD use) showed 20% to 32% decreases in PVLE losses ($1.331-$1.137 billion vs $1.664 billion), saving up to $527 million over 10 years. CONCLUSIONS: Productivity cost losses due to mortality in stage III/IV cHL are high. Increasing A+AVD use for patients with stage III/IV cHL would reduce productivity cost losses as deaths are avoided, based on ECHELON-1 OS results.
Assuntos
Doença de Hodgkin , Humanos , Estados Unidos/epidemiologia , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/patologia , Vimblastina/uso terapêutico , Bleomicina/efeitos adversos , Doxorrubicina/efeitos adversos , Dacarbazina/uso terapêutico , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
BACKGROUND: Fibroblast activation protein-α (FAPα) is a marker of activated fibroblasts that can be selectively targeted by an inhibitor (FAPI) and visualised by PET/CT imaging. We evaluated whether the measurement of FAPα in bronchoalveolar lavage fluids (BALF) and the uptake of FAPI by PET/CT could be used as biomarkers of fibrogenesis. METHODS: The dynamics of lung uptake of 18F-labeled FAPI ([18F]FAPI-74) was assessed in the bleomycin mouse model at various time points and using different concentrations of bleomycin by PET/CT. FAPα was measured in BALFs from these bleomycin-treated and control mice. FAPα levels were also assessed in BALFs from controls and patients with idiopathic pulmonary fibrosis (IPF). RESULTS: Bleomycin-treated mice presented a significantly higher uptake of [18F]FAPI-74 during lung fibrinogenesis (days 10 and 16 after instillation) compared to control mice. No significant difference was observed at initial inflammatory phase (3 days) and when fibrosis was already established (28 days). [18F]FAPI-74 tracer was unable to show a dose-response to bleomycin treatment. On the other hand, BALF FAPα levels were steeply higher in bleomycin-treated mice at day 10 and a significant dose-response effect was observed. Moreover, FAPα levels were strongly correlated with lung fibrosis as measured by the modified Aschroft histological analysis, hydroxyproline and the percentage of weight loss. Importantly, higher levels of FAPα were observed in IPF patients where the disease was progressing as compared to stable patients and controls. Moreover, patients with FAPα BALF levels higher than 192.5 pg/mL presented a higher risk of progression, transplantation or death compared to patients with lower levels. CONCLUSIONS: Our preclinical data highlight a specific increase of [18F]FAPI-74 lung uptake during the fibrotic phase of the bleomycin murine model. The measurement of FAPα in BALF appears to be a promising marker of the fibrotic activity in preclinical models of lung fibrosis and in IPF patients. Further studies are required to confirm the role of FAPα in BALF as biomarker of IPF activity and assess the relationship between FAPα levels in BALF and [18F]FAPI-74 uptake on PET/CT in patients with fibrotic lung disease.
Assuntos
Fibrose Pulmonar Idiopática , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Camundongos , Animais , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose , Líquido da Lavagem Broncoalveolar , Bleomicina/efeitos adversosRESUMO
OBJECTIVE: To evaluate the impact of bleomycin/etoposide/cisplatin (BEP) and paclitaxel/carboplatin (PC) chemotherapy regimens on the fertility and prognostic outcomes in malignant ovarian germ cell tumor (MOGCT) patients who underwent fertility-sparing surgery (FSS). METHODS: A propensity score matching algorithm was performed between the BEP and PC groups. The χ² test and the Kaplan-Meier method were used to compare the fertility outcome, disease-free survival (DFS) and overall survival (OS). The Cox proportional hazards regression analysis was used to identify risk factor of DFS. RESULTS: We included 213 patients, 185 (86.9%) underwent BEP chemotherapy, and 28 (13.1%) underwent PC chemotherapy. The median age was 22 years (range, 8-44 years), and the median follow-up period was 63 months (range, 2-191 months). Fifty-one (29.3%) patients had a pregnancy plan, and 35 (85.4%) delivered successfully. In the before and after propensity score matching cohorts, there were no significant differences in spontaneous abortion, selective termination of pregnancy, during-pregnancy status, and live birth between the BEP and PC groups (p>0.05). Fourteen (6.6%) patients experienced recurrence, including 11 (5.9%) in the BEP group and 3 (10.7%) in the PC group. Four (1.9%) patients in the BEP group died. Kaplan-Meier analysis revealed no significant differences in DFS (p=0.328) and OS (p=0.446) between the BEP and PC groups, and the same survival results were observed in the after matching cohort. CONCLUSION: The PC regimen is as safe as the BEP regimen for MOGCT patients with fertility preservation treatment, and no differences were observed in fertility and clinical prognosis.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Feminino , Humanos , Gravidez , Adulto Jovem , Adulto , Cisplatino , Etoposídeo , Carboplatina , Estudos Retrospectivos , Tratamento Conservador , Neoplasias Ovarianas/cirurgia , Bleomicina/efeitos adversos , Prognóstico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica , Paclitaxel/uso terapêuticoRESUMO
INTRODUCTION: The InPOG-HL-15-01, a multicentric prospective study, used a risk-stratified and response-based approach with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) backbone to treat children and adolescents with newly diagnosed Hodgkin lymphoma (HL) and reduce the use of radiation therapy (RT). Children/adolescents with bulky disease or inadequate response at early response assessment (ERA) after two cycles of chemotherapy were assigned to receive RT. For ERA, positron emission tomography computed tomography (PET-CT) was recommended but not mandatory in view of limited access. This study aimed to compare the impact of using contrast-enhanced computed tomography (CECT) and PET-CT on treatment decisions and outcomes. METHODOLOGY: 396 patients were enrolled and 382 had an ERA at the assigned time point. Satisfactory response was defined as Deauville score 3 or less for patients undergoing PET-CT and complete response (CR)/very good partial response (VGPR) for patients undergoing CECT. Outcomes of interest incorporate 5 year event-free survival (EFS), EFS including abandonment (EFSa), and overall survival (OS). RESULTS: At ERA, satisfactory response was documented in 277 out of 382 (72.5%) participants and this was significantly higher in PET-CT (151 out of 186, 81.2%) as compared with CECT-based assessments (126 out of 196, 64.3%) respectively (p value < .001). Amongst the 203 patients with nonbulky disease (wherein the indication for RT was entirely dependent on ERA), 96 out of 114 (84.2%) and 61 out of 89 (68.5%) patients achieved a satisfactory response according to the PET-CT and CECT (p value = .008) respectively and hence a lesser proportion of patients in the PET-CT arm received RT. Despite a lower usage of RT the 5 year OS of both groups, ERA based on CECT (91.8%) versus PET-CT (94.1%) was comparable (p value = .391) and so was the 5 year EFS (86.7 vs. 85.5%, p value = .724). CONCLUSION: Use of PET-CT as the modality for ERA is more likely to indicate a satisfactory response as compared with CECT and thereby decreases the need for RT in response-based treatment algorithm for HL-afflicted children. The reduction in the application of RT did not impact the overall outcome and plausibly would lower the risk of delayed toxic effects.
Assuntos
Doença de Hodgkin , Criança , Adolescente , Humanos , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Dacarbazina/uso terapêutico , Vimblastina/uso terapêutico , Bleomicina/efeitos adversos , Doxorrubicina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Prospectivos , Países em Desenvolvimento , Tomografia por Emissão de Pósitrons , Estadiamento de NeoplasiasRESUMO
The aim of this study is to evaluate the effect of GnRH agonist or GnRH antagonist therapy on bleomycin-administered rats by examining ovarian follicle counts and AMH levels. A total of 30 female Wistar albino rats aged 4-6 months were randomly divided into 4 groups. First, an intramuscular injection of bleomycin (30 mg/m2) was administered to all except the control group on the 1st, 8th and 15th days. The control group (Group I) was administered 0.1 mL intramuscular saline on those days. The bleomycin group (Group II) was followed up without any further treatment. The bleomycin + GnRH agonist group (Group III) was administered subcutaneous GnRH agonist triptorelin (1 mg/kg) at the same time as the bleomycin injections. The bleomycin + GnRH antagonist group (Group IV) was administered 1 mg/kg cetrorelix acetate subcutaneously, concurrently with the bleomycin. Although AMH levels were lower in the bleomycin group than in all the other groups, there was no statistically significant difference between the groups in terms of AMH levels (p > .05). In the bleomycin + cetrorelix acetate and bleomycin + triptorelin groups, significantly higher primordial, secondary and tertiary follicle counts were determined compared to the bleomycin group (p < .001). In conclusion the harmful effects of bleomycin on ovarian reserve can be reduced by the simultaneous administration of GnRH agonist or GnRH antagonist.
Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Doenças Ovarianas/prevenção & controle , Pamoato de Triptorrelina/uso terapêutico , Animais , Hormônio Antimülleriano/sangue , Antibióticos Antineoplásicos/efeitos adversos , Bleomicina/efeitos adversos , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Gonadotropina/uso terapêutico , Doenças Ovarianas/sangue , Doenças Ovarianas/induzido quimicamente , Doenças Ovarianas/patologia , Folículo Ovariano/patologia , Distribuição Aleatória , Ratos Wistar , Pamoato de Triptorrelina/farmacologiaRESUMO
Introduction: Outcomes of patients with classical Hodgkin lymphoma are excellent, and the intent of frontline therapy for even advanced-stage disease has been curative. This review summarizes the role of brentuximab vedotin in the upfront treatment of advanced stage classical Hodgkin lymphoma in the context of reducing therapy-related toxicity without compromising the high cure rate. Areas covered: Strategies to reduce bleomycin-induced lung toxicity include a response-adapted approach investigated in the RATHL study and a replacement of bleomycin with brentuximab vedotin in frontline chemotherapy regimens. In both studies, omission of bleomycin in the non-standard arms decreased the rate of pulmonary toxicity while maintaining high progression-free survival and overall survival rates. Expert opinion: The approval of A+AVD in North America offers a new bleomycin-free regimen for the treatment of advanced-stage HL, but it must be balanced against a risk-adapted approach. Recently presented subset analyses raise a question about which patients benefit most from this therapy.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Brentuximab Vedotin/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Imunotoxinas/uso terapêutico , Antineoplásicos Imunológicos/economia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/efeitos adversos , Bleomicina/economia , Brentuximab Vedotin/economia , Ensaios Clínicos como Assunto , Análise Custo-Benefício , Dacarbazina/economia , Dacarbazina/uso terapêutico , Doxorrubicina/economia , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/economia , Doença de Hodgkin/mortalidade , Humanos , Imunotoxinas/economia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Análise de Sobrevida , Vimblastina/economia , Vimblastina/uso terapêuticoRESUMO
Well-defined, humane endpoints aid in monitoring animal health status during disease development. Body condition scoring (BCS) is a method for assessing health status in mouse studies where wasting and death are potential endpoints. Whether BCS is useful in monitoring animals with bleomycin-induced lung injury has not been reported. Body weight (BW) is a common humane endpoint for this model, but because the lungs increase in weight as BW decreases, the animal's true physical condition could be masked when using BW as the sole endpoint criterion. Therefore, our goal here was to assess the usefulness of BCS in monitoring health status in a mouse model of lung injury. Lung injury was caused by acute instil- lation of the fibrogenic antibiotic bleomycin into the lungs through the trachea. Male C57BL/6 mice received bleomycin (0.075 U) dissolved in saline or saline alone. Bleomycin instillation led to a doubling of lung weight and decreases in both BW and BCS, compared with saline instillation. The changes in BW and BCS were significantly correlated with lung weight. When the adjusted BW was used (corrected for the increase in lung weight), the correlation was unchanged, suggesting that the increase in lung weight did not significantly mask the decrease in BW. Bleomycin instillation caused decreases in both soleus and visceral epididymal fat masses. The change in BCS was significantly correlated with both soleus and VEF mass, suggesting that BCS is reflective of the systemic loss of muscle and fat mass. Our findings suggest that BW and BCS are significantly correlated to lung injury in the bleomycin model of lung fibrosis and that BCS is an appropriate alternative humane endpoint in this mouse model.
Assuntos
Indicadores Básicos de Saúde , Animais , Bleomicina/efeitos adversos , Constituição Corporal/fisiologia , Peso Corporal/fisiologia , Modelos Animais de Doenças , Lesão Pulmonar/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BLAssuntos
Dermatologia/economia , Consentimento Livre e Esclarecido , Imperícia/economia , Doenças da Unha/tratamento farmacológico , Verrugas/tratamento farmacológico , Administração Tópica , Adolescente , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Criança , Dermatologia/legislação & jurisprudência , Dinitroclorobenzeno/administração & dosagem , Dinitroclorobenzeno/efeitos adversos , Feminino , Humanos , Injeções Intralesionais/efeitos adversos , Responsabilidade Legal/economia , Lidocaína/administração & dosagem , Lidocaína/efeitos adversos , Masculino , Doenças da Unha/economia , Unhas/efeitos dos fármacos , Unhas/lesões , República da Coreia , Verrugas/economiaRESUMO
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by the progressive and irreversible destruction of lung architecture, which causes significant deterioration in lung function and subsequent death from respiratory failure. The pathogenesis of IPF in experimental animal models has been induced by bleomycin administration. In this study, we investigate an IPF-like mouse model induced by a double intratracheal bleomycin instillation. Standard histological assessments used for studying lung fibrosis are invasive terminal procedures. The goal of this work is to monitor lung fibrosis through noninvasive imaging techniques such as Fluorescent Molecular Tomography (FMT) and Micro-CT. These two technologies validated with histology findings could represent a revolutionary functional approach for real time non-invasive monitoring of IPF disease severity and progression. The fusion of different approaches represents a step further for understanding the IPF disease, where the molecular events occurring in a pathological condition can be observed with FMT and the subsequent anatomical changes can be monitored by Micro-CT.
Assuntos
Bleomicina/efeitos adversos , Pulmão/patologia , Imagem Multimodal/métodos , Fibrose Pulmonar/induzido quimicamente , Tomografia Computadorizada por Raios X/métodos , Animais , Técnicas de Cultura de Células , Modelos Animais de Doenças , Progressão da Doença , Fluorescência , Estudos Longitudinais , Camundongos , Fibrose Pulmonar/patologia , Microtomografia por Raio-X/métodosRESUMO
Pulmonary rehabilitation mixture (PRM), a Chinese herbal medicine formula, has been used to treat pulmonary fibrosis for decades. In this study, we systematically evaluated the pharmacodynamic and pharmacokinetic performance of PRM. The pharmacodynamic results showed that PRM could improve the condition of CoCl2-stimulated human type II alveolar epithelial cells, human pulmonary microvascular endothelial cells, human lung fibroblasts and pulmonary fibrosis rats induced by bleomycin, PRM treatment reduced the expression of platelet-derived growth factor, fibroblast growth factor, toll-like receptor 4, high-mobility group box protein 1 and hypoxia-inducible factor 1α. In the pharmacokinetic study, an accurate and sensitive ultra-high performance liquid chromatography tandem mass spectrometry method was developed and validated for the simultaneous determination of calycosin, calycosin-7-O-glucoside, formononetin, ononin and mangiferin of PRM in the rat plasma for the first time. The method was then successfully applied to the comparative pharmacokinetic study of PRM in normal and pulmonary fibrosis rats. The five constituents could be absorbed in the blood after the oral administration of PRM and exhibited different pharmacokinetic behaviors in normal and pulmonary fibrosis rats. In summary, PRM exhibited a satisfactory pharmacodynamic and pharmacokinetic performance, which highlights PRM as a potential multi-target oral drug for the treatment of pulmonary fibrosis.
Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/reabilitação , Administração Oral , Animais , Bleomicina/efeitos adversos , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Células Endoteliais , Fibroblastos , Humanos , Masculino , Espectrometria de Massas , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , RatosRESUMO
Purpose To provide new information on adverse health outcomes (AHOs) in testicular cancer survivors (TCSs) after four cycles of etoposide and cisplatin (EPX4) or three or four cycles of bleomycin, etoposide, cisplatin (BEPX3/BEPX4). Methods Nine hundred fifty-two TCSs > 1 year postchemotherapy underwent physical examination and completed a questionnaire. Multinomial logistic regression estimated AHOs odds ratios (ORs) in relation to age, cumulative cisplatin and/or bleomycin dose, time since chemotherapy, sociodemographic factors, and health behaviors. Results Median age at evaluation was 37 years; median time since chemotherapy was 4.3 years. Chemotherapy consisted largely of BEPX3 (38.2%), EPX4 (30.9%), and BEPX4 (17.9%). None, one to two, three to four, or five or more AHOs were reported by 20.4%, 42.0%, 25.1%, and 12.5% of TCSs, respectively. Median number after EPX4 or BEPX3 was two (range, zero to nine and zero to 11, respectively; P > .05) and two (range, zero to 10) after BEPX4. When comparing individual AHOs for EPX4 versus BEPX3, Raynaud phenomenon (11.6% v 21.4%; P < .01), peripheral neuropathy (29.2% v 21.4%; P = .02), and obesity (25.5% v 33.0%; P = .04) differed. Larger cumulative bleomycin doses (OR, 1.44 per 90,000 IU) were significantly associated with five or more AHOs. Increasing age was a significant risk factor for one to two, three to four, or five or more AHOs versus zero AHOs (OR, 1.22, 1.50, and 1.87 per 5 years, respectively; P < .01); vigorous physical activity was protective (OR, 0.62, 0.51, and 0.41, respectively; P < .05). Significant risk factors for three to four and five or more AHOs included current (OR, 3.05 and 3.73) or former (OR, 1.61 and 1.76) smoking ( P < .05). Self-reported health was excellent/very good in 59.9% of TCSs but decreased as AHOs increased ( P < .001). Conclusion Numbers of AHOs after EPX4 or BEPX3 appear similar, with median follow-up of 4.3 years. A healthy lifestyle was associated with reduced number of AHOs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Obesidade/epidemiologia , Doenças do Sistema Nervoso Periférico/epidemiologia , Doença de Raynaud/epidemiologia , Sobreviventes/estatística & dados numéricos , Neoplasias Testiculares/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Canadá/epidemiologia , Estudos de Casos e Controles , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Etoposídeo/administração & dosagem , Exercício Físico , Nível de Saúde , Perda Auditiva/induzido quimicamente , Perda Auditiva/epidemiologia , Humanos , Efeitos Adversos de Longa Duração/induzido quimicamente , Efeitos Adversos de Longa Duração/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Prevalência , Fatores de Proteção , Doença de Raynaud/induzido quimicamente , Fatores de Risco , Fumar/epidemiologia , Inquéritos e Questionários , Zumbido/induzido quimicamente , Zumbido/epidemiologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Current practice guidelines are unclear regarding the role of secondary prophylaxis of febrile neutropenia in advanced-stage Hodgkin lymphoma despite several small retrospective studies that demonstrate the omission of growth factors to be a safe and economic practice. We used a decision-analytic model to compare secondary prophylaxis with granulocyte colony-stimulating factor (G-CSF) to no G-CSF with the onset of severe neutropenia for a hypothetical cohort of patients with advanced-stage Hodgkin lymphoma treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). There was a net benefit of 0.017 years and 0.037 quality-adjusted life years for no G-CSF use in severe neutropenia. On microsimulation (10 000 trials), 96% of the simulations showed that the no G-CSF strategy is preferred to the use of G-CSF. This finding was robust across a wide range of sensitivity analyses. Our analysis suggests that G-CSF not be used as secondary prophylaxis of febrile neutropenia in advanced-stage Hodgkin lymphoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Técnicas de Apoio para a Decisão , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Doença de Hodgkin/complicações , Doença de Hodgkin/tratamento farmacológico , Pré-Medicação , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Árvores de Decisões , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Cadeias de Markov , Estadiamento de Neoplasias , Anos de Vida Ajustados por Qualidade de Vida , Resultado do Tratamento , Vimblastina/efeitos adversos , Vimblastina/uso terapêuticoRESUMO
AIM: The purpose of the study was to determine the lung toxicity caused by amiodarone (AD) and bleomycin (BLM) in rats, by means of Tc-99m HMPAO lung scintigraphy. METHODS: Thirty albino rats were randomly divided into five groups. After AD or BLM was dissolved with isotonic saline (SF), a 0.5 ml solution was applied to the right bronchus via a catheter. Group 1 (n = 5 rats) received a single dose of AD, group 2 (n = 5) received two doses of AD, group 3 (n = 9) received BLM, group 4 (n = 3) received hydrochloric acid (HCl), and group 5 (n = 8) received SF. Rats in groups 1, 2, 3 and 5 were given 37 MBq Tc-99m HMPAO from the tail vein on days 7, 14, 21 and 28, and at 4 and 24 h in group 4. Static images of 10 min duration were obtained at 30 and 60 min by a double-headed gamma camera (Infinia, GE, Tirat Hacermel, Israel) on 256 × 256 matrix. Regular regions of interests were drawn over the right lung (RL), left lung (LL) and the liver (Li), and lung/liver (L/Li) ratios were calculated. After the scintigraphic imaging procedures were completed, rats were killed. Lung tissues were evaluated on a scale of (+) to (+++++) for edema, alveolar structural integrity and infiltration by inflammatory cells. RESULTS: Groups 2 and 3 showed statistically significant differences in RL/Li and LL/Li ratios, whereby RL/Li was higher than LL/Li (p < 0.05). There were no significant differences in RL/Li and LL/Li ratios in group 5 (p > 0.05). In histopathological examination, minimal damage or artifacts were observed in group 5. In group 4, almost all pathological findings were present in the right lung. Statistically significant (p < 0.01) histological differences were found when groups 1 and 5 were compared. More significant (p < 0.001) pathological effects were noted when groups 2 and 3 were compared to both groups 5 and 1. Injury was more prominent in the lung tissues of the control rats that were given HCl. Increased RL/Li ratios and histopathological findings were consistent. CONCLUSION: Tc-99m HMPAO lung scan are found to be useful in the identification of patients with lung toxicity. The simplicity of the procedure and lower radiation exposure are the advantages of Tc-99m HMPAO lung scan.
Assuntos
Amiodarona/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Bleomicina/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/diagnóstico por imagem , Tecnécio Tc 99m Exametazima , Animais , Pulmão/citologia , Masculino , Cintilografia , RatosRESUMO
Although patients with Hodgkin lymphoma treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy frequently develop neutropenia, febrile neutropenia is uncommon. Three retrospective trials reported that ABVD could be safely administered without dose delays or granulocyte-colony stimulating factor (G-CSF) support. We retrospectively reviewed the charts of 89 patients treated with ABVD and found that the incidence of febrile neutropenia was 0.5% (five of 927 treatments). This prompted a change to our institutional policy so that patients receiving ABVD no longer receive routine G-CSF for uncomplicated neutropenia. We then prospectively assessed the safety of this policy change. Thirty-three patients received a total of 327 ABVD treatments, 185 (57%) of which were administered with a neutrophil count <1.5 × 10(9)/L. Febrile neutropenia occurred in 2/33 patients (6%), complicating 0.6% of chemotherapy treatments (2/327). Eliminating routine G-CSF saved $10 241 per patient. Omission of G-CSF for uncomplicated neutropenic patients receiving ABVD for Hodgkin lymphoma is cost-saving and safe.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Análise Custo-Benefício , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Febre/induzido quimicamente , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Doença de Hodgkin/economia , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Estudos Prospectivos , Fatores de Risco , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Adulto JovemRESUMO
PURPOSE: To demonstrate the feasibility of proton MRI to noninvasively quantify bleomycin-induced injury and the effects of glucocorticosteroids in a rat model of lung fibrosis. MATERIALS AND METHODS: Sprague-Dawley rats received bleomycin intra-tracheally and underwent MRI up to day 70 following injury onset. A subgroup of animals was treated with budesonide. RESULTS: The response in the first 2 weeks post-bleomycin, characterized by diffuse MRI signals, was related primarily to inflammation as confirmed by histology. Later, increased signals reflected principally tissue remodeling involved in fibrosis development, as suggested by histological analysis revealing collagen deposition in the same areas where MRI signals had been detected. Budesonide administration at days 6 and 13 after bleomycin resulted in decreased MRI signals 24 h after each corticosteroid application. However, no complete signal resolution was observed. Histology showed that budesonide affected inflammation but not fibrosis. CONCLUSION: The ability of MRI to noninvasively quantify lung injury in bleomycin-treated rats will facilitate in vivo pharmacological studies in this model of pulmonary fibrosis. Repetitive measurements open new avenues in testing compounds as the responses at several time points during the course of treatment can be easily compared. Specifically, studies at the chronic phase, when fibrosis is already established, become amenable.
Assuntos
Bleomicina/efeitos adversos , Fibrose/induzido quimicamente , Glucocorticoides/uso terapêutico , Lesão Pulmonar/induzido quimicamente , Pulmão/efeitos dos fármacos , Imageamento por Ressonância Magnética/métodos , Animais , Antibióticos Antineoplásicos/efeitos adversos , Budesonida/efeitos adversos , Colágeno/química , Fibrose/patologia , Glucocorticoides/efeitos adversos , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
PURPOSE: Treatment efficacy and toxicity are difficult to predict in lymphoma patients. In this study, the utility of circulating biomarkers in predicting and/or monitoring treatment efficacy/toxicity were investigated. PATIENTS AND METHODS: Circulating biomarkers of cell death (nucleosomal DNA (nDNA) and cytokeratin 18 (CK18)), and circulating FLT3 ligand, a potential biomarker of myelosuppression, were assessed before and serially after standard chemotherapy in 49 patients with Hodgkin and non-Hodgkin lymphoma. Cytokeratin 18 is not expressed in lymphoma cells so is a potential biomarker of epithelial toxicity in this setting. Tumour response was assessed before and after completion of chemotherapy by 2D and 3D computed tomography radiological response. RESULTS: Baseline nDNA level was significantly higher in all lymphoma subtypes compared with 61 healthy controls and was prognostic for progression-free survival in diffuse large B-cell lymphoma (DLBCL). Decreases in nDNA levels were observed in the first week after chemotherapy; in FL, early falls in nDNA predicted for long remission following therapy. In DLBCL, elevations in nDNA occurred in cases with progressive disease. Circulating CK18 increased within 48 h of chemotherapy and was significantly higher in patients experiencing epithelial toxicity graded >3 by Common Terminology for Classification of Adverse Events criteria. FLT3 ligand was elevated within 3-8 days of chemotherapy initiation and predicted those patients who subsequently developed neutropenic sepsis. CONCLUSION: These data suggest circulating biomarkers contribute useful information regarding tumour response and toxicity in patients receiving standard chemotherapy and have potential utility in the development of individualised treatment approaches in lymphoma. These biomarkers are now being tested within multicentre phase III trials to progress their qualification.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Linfoma/diagnóstico , Linfoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Farmacológicos/análise , Biomarcadores Farmacológicos/sangue , Biomarcadores Tumorais/análise , Bleomicina/efeitos adversos , Bleomicina/farmacocinética , Bleomicina/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacocinética , Ciclofosfamida/uso terapêutico , DNA/análise , DNA/sangue , Dacarbazina/efeitos adversos , Dacarbazina/farmacocinética , Dacarbazina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Feminino , Humanos , Queratina-18/análise , Queratina-18/sangue , Linfoma/sangue , Linfoma/metabolismo , Masculino , Pessoa de Meia-Idade , Nucleossomos/genética , Valor Preditivo dos Testes , Prednisona/efeitos adversos , Prednisona/farmacocinética , Prednisona/uso terapêutico , Prognóstico , Rituximab , Vimblastina/efeitos adversos , Vimblastina/farmacocinética , Vimblastina/uso terapêutico , Vincristina/efeitos adversos , Vincristina/farmacocinética , Vincristina/uso terapêutico , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/análise , Tirosina Quinase 3 Semelhante a fms/sangueRESUMO
PURPOSE: To examine ovarian reserve following chemotherapy in women with Hodgkin's disease. METHODS: The study included nine patients who underwent ovarian tissue cryopreservation (OTCP) prior to chemotherapy consisting of the ABVD regimen (Adriamycin, bleomycin, vinblastine, and dacarbazine) and co-treatment with gonadotropin-releasing hormone agonist (GnRH-a) (Group A), and 13 patients treated by the ABVD protocol only without GnRH-a (Group B). The average age was 25.2 +/- 2.7 years for the women in Group A and 31.8 +/- 6.8 years for those in Group B. RESULTS: Six months following the end of chemotherapy, the menstrual cycle resumed in all Group A patients and in four Group B patients who had amenorrhea. Eight Group B patients had regular menses during and after chemotherapy. None of the patients suffered from ovarian failure. Two Group A patients conceived in the first year after completing chemotherapy. CONCLUSIONS: Co-treatment with GnRH-a has little effect on ovarian protection in women with Hodgkin's disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criopreservação , Hormônio Liberador de Gonadotropina/agonistas , Doença de Hodgkin/tratamento farmacológico , Ovário , Insuficiência Ovariana Primária/prevenção & controle , Adulto , Hormônio Antimülleriano/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Estudos de Coortes , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/farmacologia , Doença de Hodgkin/sangue , Humanos , Hormônio Luteinizante/sangue , Insuficiência Ovariana Primária/induzido quimicamente , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Infertility is one of the most significant side-effects in long-term survivors of successfully treated Hodgkin's lymphoma (HL). PATIENTS AND METHODS: The fertility status was assessed in male HL patients enrolled into trials of the German Hodgkin Study Group from 1988 to 2003. RESULTS: In pre-treatment analysis (n = 202), 20% of patients had normozoospermia, 11% azoospermia and 69% had other dyspermia. In post-treatment analysis (n = 112), 64% of patients had azoospermia, 30% other dyspermia and 6% normozoospermia (P < 0.001). Azoospermia was observed in 90% of patients treated with chemotherapy alone, 67% of those treated with combined modality and 11% of those treated with radiotherapy alone (P < 0.001). Azoospermia was more frequent after 4x cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (COPP/ABVD) (91%), 8x bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP) baseline (93%) and 8x BEACOPP escalated (87%) compared with 2x COPP/ABVD (56%; P = 0.003). There was a statistically significant difference in post-treatment follicle-stimulating hormone (FSH) levels between patients with azoospermia and those with preserved spermatogenesis (P = 0.001). CONCLUSIONS: Depending on the treatment received, male HL patients are at high risk of infertility after treatment. FSH might be used as surrogate parameter for male fertility in future studies.