RESUMO
BACKGROUND: The key endpoints for the assessment of the effect of maintenance therapy for metastatic colorectal cancer (mCRC) are survival and quality-of-life outcomes. We aimed to compare dermatology-related quality of life (DRQOL) in patients with RAS wild-type (wt) mCRC treated with fluorouracil and folinic acid (FU/FA) + panitumumab (Pmab) versus FU/FA alone as maintenance therapy after folinic acid, fluorouracil and oxaliplatin + Pmab induction. PATIENTS AND METHODS: The phase II randomized PanaMa (AIO KRK 0212; NCT01991873) trial included 387 patients at 70 community/academic sites in Germany. For this prespecified secondary analysis, DRQOL outcomes were assessed using the Functional Assessment of Cancer Therapy-epidermal growth factor receptor inhibitor (FACT-EGFRI), Dermatology Life Quality Index (DLQI), and Skindex-16 questionnaires at every second cycle of therapy until disease progression/death. RESULTS: At least one DRQOL questionnaire was completed by a total of 310/377 (82%) patients who received induction therapy, and by 216/248 (87%) patients who were randomized and received maintenance therapy. Patients who experienced skin toxicity according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) during induction therapy had significantly worse DRQOL according to all three measures, compared to those who did not [i.e. Skindex-16, mean difference at cycle 2 -12.87; 95% confidence interval (CI) -20.01 to -5.73; P < 0.001]. During maintenance therapy, significantly improved recovery was observed in all DRQOL measures for patients receiving FU/FA, compared to those receiving additional Pmab (i.e. Skindex-16, mean difference at cycle 6 -16.53; 95% CI -22.68 to -10.38; P < 0.001). CONCLUSIONS: In this secondary analysis of a phase II randomized clinical trial, patient-reported DRQOL outcomes correlated with skin toxicity according to NCI-CTCAE during induction therapy. Maintenance therapy with FU/FA + Pmab was associated with deteriorated DRQOL versus FU/FA alone in patients with RAS wt mCRC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Fluoruracila , Leucovorina , Panitumumabe , Qualidade de Vida , Humanos , Fluoruracila/uso terapêutico , Fluoruracila/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Masculino , Feminino , Leucovorina/uso terapêutico , Leucovorina/farmacologia , Leucovorina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Panitumumabe/uso terapêutico , Panitumumabe/farmacologia , Pessoa de Meia-Idade , Idoso , Adulto , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/farmacologiaRESUMO
BACKGROUND: Clinical trials in metastatic colorectal cancer (mCRC) are usually conducted irrespective of sex. Sex-associated differences relating to safety and efficacy in the treatment of mCRC, however, are gaining interest. METHODS: PanaMa investigated the efficacy of panitumumab (Pmab) plus fluorouracil and folinic acid (FU/FA) versus FU/FA alone after induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab in patients with RAS wild-type mCRC. In this post hoc analysis, the study population was stratified for sex. Evaluated efficacy endpoints during maintenance treatment were progression-free survival (PFS, primary endpoint of the trial), overall survival (OS) and objective response rate during maintenance therapy. Safety endpoints were rates of any grade and grade 3/4 adverse events during maintenance therapy. RESULTS: In total, 165 male and 83 female patients were randomized and treated. Male and female patients showed numerically better objective response rates with Pmab, without reaching statistical significance. Male patients derived a significant benefit from the addition of Pmab to maintenance treatment with regard to PFS [hazard ratio (HR) 0.63; 95% confidence interval (CI) 0.45-0.88; P = 0.006] that was not observed in female patients (HR 0.85; 95% CI 0.53-1.35; P = 0.491). The better PFS for male patients treated with Pmab did not translate into improved OS (HR 0.85; 95% CI 0.55-1.30; P = 0.452). Female patients showed numerically improved OS when treated with Pmab. There was no difference in the total of grade ≥3 adverse events during maintenance regarding sex (P = 0.791). Female patients, however, had a higher rate of any grade nausea, diarrhea and stomatitis. CONCLUSIONS: In the PanaMa trial, the addition of Pmab to maintenance treatment of RAS wild-type mCRC with FU/FA improved the outcome in terms of the primary endpoint (PFS) particularly in male patients. Female patients did not show the same benefit while experiencing higher rates of adverse events. Our results support the development of sex-specific protocols.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Masculino , Feminino , Panitumumabe/farmacologia , Panitumumabe/uso terapêutico , Leucovorina/efeitos adversos , Neoplasias Colorretais/patologia , Resultado do Tratamento , Fluoruracila/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The X-linked dominant CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects) is a rare developmental defect characterized by a strictly lateralized inflammatory nevus. In the majority of cases, the right side of the body is affected. Ipsilateral hypoplastic lesions may involve the brain, skeletal structures, lungs, heart or kidneys. We describe a case of CHILD syndrome involving the left side of the body. Absence of metacarpal, metatarsal and phalangeal bones of the left hand and foot resulted in oligodactyly, with only 3 fingers and 1 toe. An ipsilateral inflammatory epidermal nevus with hyperkeratosis, parakeratosis, acanthosis and perivascular lymphohistiocytic infiltrate was strictly confined to the left half of the patient's body. The phenotype was shown to be associated with a deletion of exons 6-8 of the X-linked NSDHL gene, confirming that CHILD syndrome is due to loss of function of an enzyme involved in cholesterol biosynthesis.
Assuntos
3-Hidroxiesteroide Desidrogenases/genética , Anormalidades Múltiplas/diagnóstico , Deleção Cromossômica , Cromossomos Humanos Par 6 , Eritrodermia Ictiosiforme Congênita/genética , Deformidades Congênitas dos Membros/diagnóstico , Anormalidades Múltiplas/genética , Sequência de Bases , Pré-Escolar , Cromossomos Humanos Par 8 , Análise Mutacional de DNA , Éxons/genética , Feminino , Seguimentos , Humanos , Hidroxiesteroide Desidrogenases/genética , Eritrodermia Ictiosiforme Congênita/diagnóstico , Deformidades Congênitas dos Membros/genética , Dados de Sequência Molecular , Reação em Cadeia da Polimerase/métodos , SíndromeRESUMO
This study compared the behaviour of pathogenic bacteria (Salmonella and Listeria), faecal indicators (faecal coliforms FC and faecal streptococci FS), somatic coliphages and F-specific bacteriophages in an urban river contaminated with domestic sewage and surface run-off from agricultural and cattle grazing lands. The influence of physical and chemical parameters was also investigated as well as Salmonella and Listeria serotype diversity and drug resistance patterns. Faecal contamination was high (FC = 5 x 10(6) - 4 x 10(3) CFU/100 mL; FS = 4 x 10(5) - 2 x 10(2) CFU/100 mL) but decreased along the river by up to 99.5% following 47% reduction of BOD5 and 91% increase of DO, both associated with the self purification process. Somatic coliphages (6.9 x 10(5) - 1 x 10(3) PFU/100 mL) and F-specific bacteriophages (5.8 x 10(4) - 65 PFU/100 mL) behaved similarly with reductions of 99.85%. Salmonella and Listeria were isolated at all sampling points with highestfrequencies (91-100%) at those with sewage discharge and rural water run-off. The lowest value (35%) occurred at the end of the river where it was (a) wider and shallower, (b) it ran slower and was warmer (29-33 degrees C), (c) the pH was alkaline (8.2-9.9), (d) electrical conductivity (2,200-5,800 microS/cm) and DO (6-13 mg/L) were highest. Pathogen decline did not follow exactly FC and FS reduction patterns, while physical and chemical parameters apparently did not interfere with Salmonella and Listeria survival to the same extent as they did with FC and FS. Somatic coliphages and F-specific bacteriophages did not show more resistance than bacterial indicators. Catchment area contribution seemed to be more significant for pathogens than for indicators and rainy periods increased pathogenic isolation frequency. Five Salmonella serotypes and five serogroups were identified. S. hadar and serogroup E were predominant (50%); both are increasing in Brazil apparently from animal sources. Nearly 25% of Salmonella strains were resistant to at least one of twelve antimicrobials tested. Resistance to tetracycline was common (17%) followed by cefalotine (3%). Five Listeria serogroups were isolated and L. grayi (43%) and L. monocytogenes (9%) were present at all points. Listeria drug resistance rates were 100% for oxaciline followed by clindamicine (97%), tetracycline (34%) and vancomycin (32%). Both pathogenic bacterial strains presented resistance to the same drugs observed in humans and warm blood animals but the high number of sensitive strains and the low numbers of strains resistant to more than one drug was not expected because of the heavy anthropogenic impact in this basin.
Assuntos
Fezes/microbiologia , Listeria/isolamento & purificação , Salmonella/isolamento & purificação , Microbiologia da Água , Abastecimento de Água , Agricultura , Animais , Bacteriófagos/isolamento & purificação , Bacteriófagos/patogenicidade , Brasil , Colífagos/isolamento & purificação , Colífagos/patogenicidade , Resistência Microbiana a Medicamentos , Enterobacteriaceae/isolamento & purificação , Enterobacteriaceae/patogenicidade , Monitoramento Ambiental , Humanos , Listeria/patogenicidade , Medição de Risco , Salmonella/patogenicidade , Esgotos , Streptococcus/isolamento & purificação , Streptococcus/patogenicidadeRESUMO
The efficiencies of a natural Typha spp wetland (Wn) formed on a river bed and its effluent treatment in a constructed wetland (Wc, subsurface horizontal flow) were investigated in northeastern Brazil (Paraiba State). The Wc system (12 tanks with stone gravel, 4.13 m2, 0.22 m3, 20 Typha spp rhizomes, m(-2) each, with 38, 29, and 19 mm x d(-1) hydraulic loadings, and 5, 7, and 10 days HRT) was fed daily with effluent from a Wn. Wn removal presented the highest values after Typha spp were cut during the 5th week. Removal values were (1st and 2nd periods or before and after cutting): 75% and 81% BOD5; 10-53% total phosphorus; 13%-55% ammonia; 89%-91% FC; 90-96% coliphages and bacteriophages. Wc removals increased with time with best results on 10 d HRT. Removals were also higher in the 2nd period: 74%-78% BOD5; 58%-82% ammonia; 90% FC; 94-98% FS; and 92%-96% coliphages and bacteriophages. Despite the high remaining values of FC (1.4 x 10(4) CFU/100 ml) and FX (4 x 10(3) CFU/100 ml), the removals were satisfactory and HRT dependent, suggesting a gradual optimization of the system with time. The Wc exhibited good efficiency for improving water quality from polluted river.
Assuntos
Ecossistema , Microbiologia da Água , Poluição da Água/prevenção & controle , Brasil , Conservação dos Recursos Naturais , Filtração , Plantas , Clima Tropical , Movimentos da ÁguaRESUMO
OBJECTIVE: To assess the role of granulocyte colony-stimulating factor (G-CSF) in autoimmune neutropenia (AIN). DESIGN: Serum G-CSF levels were measured in 57 children with AIN. Two different G-CSF-dependent assays were used: a solid-phase "sandwich" enzyme-linked immunosorbent assay and a proliferation assay. Sera from healthy persons and from patients with severe congenital neutropenia were used for negative and positive controls. RESULTS: The median G-CSF level in healthy persons (n = 13) was low, 45.6 pg/mL (range <39 to 141 pg/mL). The median G-CSF level in patients with AIN (n = 57) was very similar, 45.5 pg/mL (range <39 to 2500 pg/mL). Forty-five (79%) of 57 patients with AIN had levels within the range of the control group. Seven (12%) had marginally increased G-CSF levels (141 to 400 pg/mL), and only 5 (9%) had levels higher than 400 pg/mL. The G-CSF levels measured by enzyme-linked immunosorbent assay correlated well with levels measured by the proliferation assay, thus demonstrating that antibodies present in patient sera did not affect the biologic activity of G-CSF. CONCLUSION: G-CSF production in AIN is not increased despite the low neutrophil count, similar to thrombopoietin in immune thrombocytopenic purpura.