RESUMO
PURPOSE: Diagnostic tonsillectomy is rarely an oncologic operation owing to close or positive margins. The standard of care is for further treatment to the primary site, typically with adjuvant radiotherapy. METHODS: 14 patients with close or positive margins following a diagnostic tonsillectomy underwent transoral robotic surgery (TORS) and lateral oropharyngectomy; five patients with the longest follow-up had their excision specimens examined with a step serial sectioning technique (SSS). RESULTS: Conventional histopathological examination of the TORS resection specimens did not demonstrate residual carcinoma in 13 patients, confirmed by examination using SSS in 5 patients. There were no post-operative complications or long-term functional deficit. Seven patients received surgery alone with 100% overall and disease specific survival, respectively (median follow-up 27.5 months; range 5.2-50.4). CONCLUSIONS: This prospective study suggests that TORS lateral oropharyngectomy alone is an oncologically safe treatment when close or positive margins are identified on diagnostic tonsillectomy in HPV-positive SCC.
Assuntos
Carcinoma de Células Escamosas/cirurgia , Neoplasias Orofaríngeas/cirurgia , Infecções por Papillomavirus/patologia , Faringectomia , Procedimentos Cirúrgicos Robóticos , Tonsilectomia , Idoso , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Células Epiteliais/patologia , Feminino , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/complicações , Estudos Prospectivos , Radioterapia AdjuvanteRESUMO
BACKGROUND: Bevacizumab, a monoclonal antibody that targets VEGF, has shown restricted activity in patients with advanced melanoma. We aimed to assess the role of bevacizumab as adjuvant treatment for patients with resected melanoma at high risk of recurrence. We report results from the preplanned interim analysis. METHODS: We did a multicentre, open-label, randomised controlled phase 3 trial at 48 centres in the UK between July 18, 2007, and March 29, 2012. Patients aged 16 years or older with American Joint Committee on Cancer stage (AJCC) stage IIB, IIC, and III cutaneous melanoma were randomly allocated (1:1), via a central, computer-based minimisation procedure, to receive intravenous bevacizumab 7.5 mg/kg, every 3 weeks for 1 year, or to observation. Randomisation was stratified by Breslow thickness of the primary tumour, N stage according to AJCC staging criteria, ulceration of the primary tumour, and patient sex. The primary endpoint was overall survival; secondary endpoints included disease-free interval, distant-metastases interval and quality of life. Analysis was by intention-to-treat. This trial is registered as an International Standardised Randomised Controlled Trial, number ISRCTN81261306. FINDINGS: 1343 patients were randomised to either the bevacizumab group (n=671) or the observation group (n=672). Median follow-up was 25 months (IQR 16-37) in the bevacizumab group and 25 months (17-37) in the observation group. At the time of interim analysis, 286 (21%) of 1343 enrolled patients had died: 140 (21%) of 671 patients in the bevacizumab group, and 146 (22%) of 672 patients in the observation group. 134 (96%) of patients in the bevacizumab group died because of melanoma versus 139 (95%) in the observation group. We noted no significant difference in overall survival between treatment groups (hazard ratio [HR] 0.97, 95% CI 0.78-1.22; p=0.76); this finding persisted after adjustment for stratification variables (HR 1.03; 95% CI 0.81-1.29; p=0.83). Median duration of treatment with bevacizumab was 51 weeks (IQR 21-52) and dose intensity was 86% (41-96), showing good tolerability. 180 grade 3 or 4 adverse events were recorded in 101 (15%) of 671 patients in the bevacizumab group, and 36 (5%) of 672 patients in the observation group. Bevacizumab resulted in a higher incidence of grade 3 hypertension than did observation (41 [6%] vs one [<1%]). There was an improvement in disease-free interval for patients in the bevacizumab group compared with those in the observation group (HR 0.83, 95% CI 0.70-0.98, p=0.03), but no significant difference between groups for distant-metastasis-free interval (HR 0.88, 95% CI 0.73-1.06, p=0.18). No significant differences were noted between treatment groups in the standardised area under the curve for any of the quality-of-life scales over 36 months. Three adverse drug reactions were regarded as both serious and unexpected: one patient had optic neuritis after the first bevacizumab infusion, a second patient had persistent erectile dysfunction, and a third patient died of a haemopericardium after receiving two bevacizumab infusions and was later identified to have had significant predisposing cardiovascular risk factors. INTERPRETATION: Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Modelos de Riscos Proporcionais , Fatores de Risco , Neoplasias Cutâneas/mortalidade , Adulto JovemRESUMO
BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 2, 2002 and previously updated in 2004, 2007 and 2010.Radiotherapy, open surgery and endolaryngeal excision (with or without laser) are all accepted modalities of treatment for early-stage glottic cancer. Case series suggest that they confer a similar survival advantage, however radiotherapy and endolaryngeal surgery offer the advantage of voice preservation. There has been an observed trend away from open surgery in recent years, however equipoise remains between radiotherapy and endolaryngeal surgery as both treatment modalities offer laryngeal preservation with similar survival rates. Opinions on optimal therapy vary across disciplines and between countries. OBJECTIVES: To compare the effectiveness of open surgery, endolaryngeal excision (with or without laser) and radiotherapy in the management of early glottic laryngeal cancer. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 8); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 18 September 2014. SELECTION CRITERIA: Randomised controlled trials comparing open surgery, endolaryngeal resection (with or without laser) and radiotherapy. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified only one randomised controlled trial, which compared open surgery and radiotherapy in 234 patients with early glottic laryngeal cancer. The overall risk of bias in this study was high.For T1 tumours, the five-year survival was 91.7% following radiotherapy and 100% following surgery and for T2 tumours, 88.8% following radiotherapy and 97.4% following surgery. There were no significant differences in survival between the two groups.For T1 tumours, the five-year disease-free survival rate was 71.1% following radiotherapy and 100.0% following surgery, and for the T2 tumours, 60.1% following radiotherapy and 78.7% following surgery. Only the latter comparison was statistically significant (P value = 0.036), but statistical significance would not have been achieved with a two-sided test.Data were not available on side effects, quality of life, voice outcomes or cost.We identified no randomised controlled trials that included endolaryngeal surgery. A number of trials comparing endolaryngeal resection and radiotherapy have terminated early because of difficulty recruiting participants. One randomised controlled trial is still ongoing. AUTHORS' CONCLUSIONS: There is only one randomised controlled trial comparing open surgery and radiotherapy but its interpretation is limited because of concerns about the adequacy of treatment regimens and deficiencies in the reporting of the study design and analysis.
Assuntos
Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/cirurgia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Glote/cirurgia , Humanos , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/patologia , Terapia a Laser , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
This study is based on the evidence that immunization of macaques with human CD4(+) T cells elicits prevention of simian immunodeficiency virus (SIV) infection. We hypothesized that heat-shock protein 70 (HSP70) isolated from CD4(+) T cells may act as a chaperone and carry the protective host proteins. Two moieties of HSP70 were affinity-purified from human CD4(+) T cells; an ADP preparation with HSP70-bound proteins (ADP-HSP) and an ATP control preparation. Immunization of rhesus macaques with these preparations showed significant inhibition of SIVmac251 infectivity ex vivo in CD4(+) T cells only with the ADP-HSP (P = 0.01). Proteomic analysis identified three cytoskeletal elements, cofilin, profilin and gamma-actin, exclusively in the ADP-HSP preparation. Investigation of the mechanism of prevention of SIV replication suggests that antibodies to the cytoskeletal proteins may inhibit actin depolymerization and facilitate viral degradation by the innate antiviral APOBEC3G. As cytoskeletal proteins are critical in the formation of virological and immunological synapses, finding specific antibodies and anti-SIV/human immunodeficiency virus (HIV) factors suggests a novel insight into HIV-1 immunopathogenesis.
Assuntos
Fatores de Despolimerização de Actina/metabolismo , Actinas/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Proteínas de Choque Térmico HSP70/metabolismo , Profilinas/metabolismo , Vírus da Imunodeficiência Símia/imunologia , Desaminase APOBEC-3G , Fatores de Despolimerização de Actina/química , Actinas/química , Animais , Sítios de Ligação , Citidina Desaminase/imunologia , Eletroforese em Gel Bidimensional , Proteínas de Choque Térmico HSP70/química , Proteínas de Choque Térmico HSP70/isolamento & purificação , Humanos , Macaca , Espectrometria de Massas , Testes de Neutralização , Profilinas/química , Vírus da Imunodeficiência Símia/isolamento & purificação , Replicação Viral/imunologiaRESUMO
Increasing antibiotic resistance has prompted development of alternative approaches to antimicrobial therapy, including blocking microbial adhesion to host receptors. The BabA adhesin of Helicobacter pylori binds to fucosylated blood group antigens, such as the Lewis(b) antigens in human primate gastric mucosa. We have isolated a human domain antibody specific for BabA that inhibits binding of BabA to Lewis(b) and prevents adhesion of H. pylori to human gastric epithelium. In addition, Lewis(b) oligosaccharides covalently linked to poly-D-lysine inhibited BabA binding to Le(b). The poly-D-lysine-Le(b) hexasaccharide and an Le(b) human serum albumin conjugate not only inhibited adherence of H. pylori to gastric epithelium but also displaced adherent bacteria when added to human stomach sections. Combinations of Le(b) and sialyl Le(x) or domain antibody 25 and sialyl Le(x) acted synergistically. Domain antibody 25 inhibitor may have potential for prophylactic use and, in combination with Le(b) glycoconjugates, therapeutic use in treatment of drug-resistant H. pylori infection.
Assuntos
Adesinas Bacterianas/imunologia , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Região Variável de Imunoglobulina/imunologia , Antígenos do Grupo Sanguíneo de Lewis/imunologia , Especificidade de Anticorpos , Mucosa Gástrica/imunologia , Mucosa Gástrica/microbiologia , Humanos , Imunização Passiva , Técnicas In Vitro , Estômago/imunologia , Estômago/microbiologiaRESUMO
Magnetic resonance imaging (MRI) offers superior soft-tissue contrast as compared with computed tomography (CT), which is conventionally used for radiation therapy treatment planning (RTP) and patient positioning verification, resulting in improved target definition. The 2 modalities are co-registered for RTP; however, this introduces a systematic error. Implementing an MRI-only radiation therapy workflow would be advantageous because this error would be eliminated, the patient pathway simplified, and patient dose reduced. Unlike CT, in MRI there is no direct relationship between signal intensity and electron density; however, various methodologies for MRI-only RTP have been reported. A systematic review of these methods was undertaken. The PRISMA guidelines were followed. Embase and Medline databases were searched (1996 to March, 2017) for studies that generated synthetic CT scans (sCT)s for MRI-only radiation therapy. Sixty-one articles met the inclusion criteria. This review showed that MRI-only RTP techniques could be grouped into 3 categories: (1) bulk density override; (2) atlas-based; and (3) voxel-based techniques, which all produce an sCT scan from MR images. Bulk density override techniques either used a single homogeneous or multiple tissue override. The former produced large dosimetric errors (>2%) in some cases and the latter frequently required manual bone contouring. Atlas-based techniques used both single and multiple atlases and included methods incorporating pattern recognition techniques. Clinically acceptable sCTs were reported, but atypical anatomy led to erroneous results in some cases. Voxel-based techniques included methods using routine and specialized MRI sequences, namely ultra-short echo time imaging. High-quality sCTs were produced; however, use of multiple sequences led to long scanning times increasing the chances of patient movement. Using nonroutine sequences would currently be problematic in most radiation therapy centers. Atlas-based and voxel-based techniques were found to be the most clinically useful methods, with some studies reporting dosimetric differences of <1% between planning on the sCT and CT and <1-mm deviations when using sCTs for positional verification.
Assuntos
Imageamento por Ressonância Magnética/métodos , Posicionamento do Paciente , Planejamento da Radioterapia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Densidade Óssea , Osso e Ossos/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Criança , Elétrons , Humanos , Imageamento por Ressonância Magnética/classificação , Masculino , Neoplasias da Próstata/diagnóstico por imagem , Prótons , Melhoria de Qualidade , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/classificaçãoRESUMO
Lactobacilli have previously been used to deliver vaccine components for active immunization in vivo. Vectors encoding a single-chain Fv (scFv) antibody fragment, which recognizes the streptococcal antigen I/II (SAI/II) adhesion molecule of Streptococcus mutans, were constructed and expressed in Lactobacillus zeae (American Type Culture Collection (ATCC) 393). The scFv antibody fragments secreted into the supernatant or expressed on the surface of the bacteria showed binding activity against SAI/II in enzyme-linked immunosorbent assay (ELISA), and surface scFv-expressing lactobacilli agglutinated SAI/II-expressing S. mutans in vitro without affecting the corresponding SAI/II knockout strain. Lactobacilli expressing the scFv fragment fused to an E-tag were visualized by scanning electron microscopy (SEM) using beads coated with a monoclonal anti-E-tag antibody, and they bound directly to beads coated with SAI/II. After administration of scFv-expressing bacteria to a rat model of dental caries development, S. mutans bacteria counts and caries scores were markedly reduced. As lactobacilli are generally regarded as safe (GRAS) microorganisms, this approach may be of considerable commercial interest for in vivo immunotherapy.
Assuntos
Regulação Bacteriana da Expressão Gênica , Região Variável de Imunoglobulina/biossíntese , Lacticaseibacillus casei/genética , Lacticaseibacillus casei/imunologia , Animais , Cárie Dentária/imunologia , Cárie Dentária/prevenção & controle , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/imunologia , Modelos Genéticos , Ratos , Ratos Sprague-Dawley , Streptococcus mutans/imunologia , Streptococcus mutans/fisiologiaAssuntos
Neoplasias de Cabeça e Pescoço , Taxoides , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab , Quimioterapia Combinada , Fluoruracila/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Taxoides/uso terapêuticoRESUMO
There is increasing interest in MR-only radiotherapy planning since it provides superb soft-tissue contrast without the registration uncertainties inherent in a CT-MR registration. However, MR images cannot readily provide the electron density information necessary for radiotherapy dose calculation. An algorithm which generates synthetic CTs for dose calculations from MR images of the prostate using an atlas of 3 T MR images has been previously reported by two of the authors. This paper aimed to evaluate this algorithm using MR data acquired at a different field strength and a different centre to the algorithm atlas. Twenty-one prostate patients received planning 1.5 T MR and CT scans with routine immobilisation devices on a flat-top couch set-up using external lasers. The MR receive coils were supported by a coil bridge. Synthetic CTs were generated from the planning MR images with ([Formula: see text]) and without (sCT) a one voxel body contour expansion included in the algorithm. This was to test whether this expansion was required for 1.5 T images. Both synthetic CTs were rigidly registered to the planning CT (pCT). A 6 MV volumetric modulated arc therapy plan was created on the pCT and recalculated on the sCT and [Formula: see text]. The synthetic CTs' dose distributions were compared to the dose distribution calculated on the pCT. The percentage dose difference at isocentre without the body contour expansion (sCT-pCT) was [Formula: see text] and with ([Formula: see text]-pCT) was [Formula: see text] (mean ± one standard deviation). The [Formula: see text] result was within one standard deviation of zero and agreed with the result reported previously using 3 T MR data. The sCT dose difference only agreed within two standard deviations. The mean ± one standard deviation gamma pass rate was [Formula: see text] for the sCT and [Formula: see text] for the [Formula: see text] (with [Formula: see text] global dose difference and [Formula: see text] distance to agreement gamma criteria). The one voxel body contour expansion improves the synthetic CT accuracy for MR images acquired at 1.5 T but requires the MR voxel size to be similar to the atlas MR voxel size. This study suggests that the atlas-based algorithm can be generalised to MR data acquired using a different field strength at a different centre.
Assuntos
Algoritmos , Imageamento por Ressonância Magnética , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Guiada por Imagem , Tomografia Computadorizada por Raios X , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Radioterapia de Intensidade ModuladaRESUMO
The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.
Assuntos
Adesinas Bacterianas/metabolismo , Aderência Bacteriana , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Mucosa Gástrica/patologia , Infecções por Helicobacter/patologia , Concentração de Íons de HidrogênioRESUMO
Anti-retroviral (ARV) -based microbicides are one of the strategies pursued to prevent HIV-1 transmission. Delivery of ARV drugs to subepithelial CD4+ T cells at concentrations for protection is likely determined by drug transporters expressed in the cervicovaginal epithelium. To define the role of drug transporters in mucosal disposition of topically applied ARV-based microbicides, these must be tested in epithelial cell line-based biopharmaceutical assays factoring the effect of relevant drug transporters. We have characterised gene expression of influx and efflux drug transporters in a panel of cervicovaginal cell lines and compared this to expression in cervicovaginal tissue. We also investigated the effect of dapivirine, darunavir and tenofovir, currently at advanced stages of microbicides development, on expression of drug transporters in cell lines. Expression of efflux ABC transporters in cervical tissue was best represented in HeLa, Ect1/E6E7 and End1/E6E7 cell lines. Expression of influx OCT and ENT transporters in ectocervix matched expression in Hela while expression of influx SLCO transporters in vagina was best reflected in VK2/E6E7 cell line. Stimulation with darunavir and dapivirine upregulated MRP transporters, including MRP5 involved in transport of tenofovir. Dapivirine also significantly downregulated tenofovir substrate MRP4 in cervical cell lines. Treatment with darunavir and dapivirine showed no significant effect on expression of BCRP, MRP2 and P-glycoprotein implicated in efflux of different ARV drugs. Darunavir strongly induced expression in most cell lines of CNT3 involved in cell uptake of nucleotide/nucleoside analogue reverse transcriptase inhibitors and SLCO drug transporters involved in cell uptake of protease inhibitors. This study provides insight into the suitability of cervicovaginal cell lines for assessment of ARV drugs in transport kinetics studies. The modulatory effect of darunavir and dapivirine on expression of drug transporters involved in transport of tenofovir points to the possibility of combining these drugs to improve retention of individual drugs at target tissues.
Assuntos
Fármacos Anti-HIV/farmacologia , Colo do Útero/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Membrana Transportadoras/biossíntese , Vagina/efeitos dos fármacos , Adulto , Transporte Biológico , Linhagem Celular , Linhagem Celular Tumoral , Colo do Útero/citologia , Colo do Útero/metabolismo , Darunavir/farmacologia , Resistência a Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos , Pirimidinas/farmacologia , Tenofovir/farmacologia , Vagina/citologia , Vagina/metabolismoRESUMO
BACKGROUND: Local and/or regional recurrence and metachronous primary tumor arising in a previously irradiated area are rather frequent events in patients with head and neck squamous cell carcinoma (HNSCC). Re-treatment is associated with an increased risk of serious toxicity and impaired quality of life (QOL) with an uncertain survival advantage. METHODS: We analyzed the literature on the efficacy and toxicity of photon/electron-based external beam reirradiation for previously irradiated patients with HNSCC of non-nasopharyngeal origin. Studies were grouped according to the radiotherapy technique used for reirradiation. Patient selection criteria, target volume identification method, tumor dose, fractionation schedule, systemic therapy administration, and toxicities were reviewed. RESULTS: In addition to disease-related factors, current comorbidities and preexisting organ dysfunction must be considered when selecting patients for reirradiation. As morbidity from re-treatment may be considerable and differ depending on which mode of re-treatment is used, it is important to give patients information on potential morbidity outcomes so that an informed choice can be made within a shared decision-making context. With improved dose distribution and adequate imaging support, including positron emission tomography-CT, modern radiotherapy techniques may improve local control and reduce toxicity of reirradiation. A reirradiation dose of ≥60 Gy and a volume encompassing the gross tumor with up to a 5-mm margin are recommended. Concomitant administration of systemic therapeutics and reirradiation is likely to be of similar benefit as observed in large randomized studies of upfront therapy. CONCLUSION: Reirradiation, administered either with or without concurrent systemic therapy, is feasible and tolerable in properly selected patients with recurrent or a new primary tumor in a previously irradiated area of the head and neck, offering a meaningful survival (in the range of 10% to 30% at 2 years). Whenever feasible, salvage surgery is the method of choice for curative intent; patients at high-risk for local recurrence should be advised that postoperative reirradiation is expected to increase locoregional control at the expense of higher toxicity and without survival advantage compared to salvage surgery without reirradiation. © 2014 Wiley Periodicals, Inc. Head Neck 37: 134-150, 2015.
Assuntos
Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/radioterapia , Recidiva Local de Neoplasia/radioterapia , Segunda Neoplasia Primária/radioterapia , Humanos , Seleção de Pacientes , Dosagem Radioterapêutica , Radioterapia Assistida por Computador , Retratamento , Terapia de Salvação , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
OBJECTIVE: To develop a novel SIV-CCR5 receptor vaccine strategy that will protect macaques from SHIV infection by the vaginal mucosal route. DESIGN: The rationale for this strategy is that humans who express the homozygous delta32 CCR5 mutation and the associated upregulation of CC chemokines, the down-modulation of cell-surface expression of CCR5 and antibodies to CCR5 are protected against HIV infection. METHODS: A vaccine was prepared consisting of three extracellular peptides of CCR5, an N-terminal HIV gp120 fragment generated in transgenic plants and recombinant SIV p27. These were linked to the 70 000 Mr microbial heat shock protein (HSP70) carrier. The vaccine was administered (x3) either by the vaginal mucosal route or by targeting the proximity of the draining iliac lymph nodes. RESULTS: Serum and vaginal fluid IgG and IgA antibodies, IL-2 and IFN-gamma-producing cells, and macrophage-inflammatory protein (MIP) 1beta and MIP-1alpha (CCL4 and CCL3) were significantly raised in immunized macaques (P = 0.01-0.05). Vaginal challenge with SHIV(89.6P) infected all macaques, but sequential analysis over 24 weeks showed a significant variation in viral loads between the animals (P = 0.05). Whereas SHIV(89.6P) persisted in the four unimmunized macaques, in five of the eight immunized macaques the virus was cleared or became undetectable by reverse transcriptase-polymerase chain reaction. The CD4 cell counts in the immunized macaques were significantly higher than those in unimmunized animals (P < 0.05). CONCLUSION: An immunization strategy that targets both the virus and its CCR5 receptor has significantly inhibited SHIV(89.6P) infection and may serve as a novel strategy in the prevention of HIV transmission.
Assuntos
Vacinas contra a AIDS/uso terapêutico , Receptores CCR5/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Animais , Anticorpos Antivirais/análise , Biomarcadores/análise , Contagem de Linfócito CD4 , Quimiocina CCL5/análise , Feminino , Infecções por HIV/imunologia , Imunoglobulina G/análise , Imunoglobulina M/análise , Interferon gama/análise , Interleucina-2/análise , Linfonodos/imunologia , Macaca mulatta , Proteínas Inflamatórias de Macrófagos/análise , Mucosa/imunologia , Receptores CCR5/análise , Linfócitos T/imunologia , Vagina/imunologia , Carga ViralRESUMO
Mannose-binding C-type lectin receptors, expressed on Langerhans cells and subepithelial dendritic cells (DCs) of cervico-vaginal tissues, play an important role in HIV-1 capture and subsequent dissemination to lymph nodes. DC-SIGN has been implicated in both productive infection of DCs and the DC-mediated trans infection of CD4(+) T cells that occurs in the absence of replication. However, the molecular events that underlie this efficient transmission have not been fully defined. In this study, we have examined the effect of the extracellular domains of DC-SIGN and Langerin on the stability of the interaction of the HIV-1 envelope glycoprotein with CD4 and also on replication in permissive cells. Surface plasmon resonance analysis showed that DC-SIGN increases the binding affinity of trimeric gp140 envelope glycoproteins to CD4. In contrast, Langerin had no effect on the stability of the gp140:CD4 complex. In vitro infection experiments to compare DC-SIGN enhancement of CD4-dependent and CD4-independent strains demonstrated significantly lower enhancement of the CD4-independent strain. In addition DC-SIGN increased the relative rate of infection of the CD4-dependent strain but had no effect on the CD4-independent strain. DC-SIGN binding to the HIV envelope protein effectively increases exposure of the CD4 binding site, which in turn contributes to enhancement of infection.
Assuntos
Antígenos CD4/metabolismo , Linfócitos T CD4-Positivos/virologia , Moléculas de Adesão Celular/fisiologia , Proteína gp120 do Envelope de HIV/metabolismo , Proteína gp41 do Envelope de HIV/metabolismo , HIV-1/metabolismo , Lectinas Tipo C/fisiologia , Receptores de Superfície Celular/fisiologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo , Anticorpos Monoclonais/química , Sítios de Ligação , Citometria de Fluxo/métodos , Perfilação da Expressão Gênica , Regulação Viral da Expressão Gênica , Humanos , Cinética , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Ressonância de Plasmônio de SuperfícieRESUMO
Fibrodysplasia ossificans progressiva (FOP) is a rare condition of ectopic calcification leading to increasing disability throughout life, with most patients being wheelchair bound by the age of 30. Ectopic calcification can be triggered by trauma and it is therefore important to minimize biopsies and operative procedures in affected individuals. We report a 46-year-old FOP patient who was successfully treated with radiotherapy for a basal cell carcinoma. There are no previous reports in the literature on the management of skin malignancies in these patients and very limited literature on outcome following external beam radiotherapy.
Assuntos
Carcinoma Basocelular/radioterapia , Miosite Ossificante/complicações , Neoplasias Cutâneas/radioterapia , Carcinoma Basocelular/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/complicaçõesRESUMO
BACKGROUND: Head and neck sarcomas are extremely rare. This article reviews the management and outcomes in a multidisciplinary clinic. METHODS: The records of 41 male and 19 female patients (mean age, 50 years) were reviewed. Forty percent underwent surgical resection only, 35% underwent surgery and adjuvant therapy, and 25% underwent radiotherapy and/or chemotherapy without surgery. Seventy-one percent had complete histologic clearance. RESULTS: The mean follow-up was 3 years and 10 months, with an overall 5-year survival rate of 60%. Completeness of surgical excision was highly significant in determining 5-year local control (p < .025), and the addition of adjuvant radiotherapy had a major effect on local control, but only if complete surgical clearance had been achieved (p < .025). As expected, patients with more aggressive tumors had a significantly poorer overall prognosis, and achieving local control led to an enhanced 5-year survival (p < .025). CONCLUSION: These tumors are best managed in multidisciplinary clinics, and the mainstay of treatment is wide local excision and planned postoperative adjuvant radiotherapy.
Assuntos
Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/terapia , Equipe de Assistência ao Paciente , Sarcoma/mortalidade , Sarcoma/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida , Reino Unido/epidemiologiaRESUMO
The antigen I/II (AgI/II) family polypeptides, ranging from 1310 to 1653 amino acid (aa) residues, are cell wall anchored adhesins expressed by most indigenous species of oral streptococci. The polypeptides interact with a wide range of host molecules, in particular salivary agglutinin glycoprotein (SAG or gp340), and with ligands on other oral bacteria. To determine the receptor recognition properties of six different AgI/II family polypeptides from strains of Streptococcus gordonii, Streptococcus intermedius and Streptococcus mutans, the genes were cloned and expressed on the surface of the surrogate host Lactococcus lactis. The S. gordonii SspA and SspB polypeptides mediated higher binding levels of L. lactis cells to surface immobilized gp340 than did S. intermedius Pas protein, or S. mutans SpaP or PAc proteins. However, the AgI/II proteins were all similar in their abilities to mediate aggregation of lactococci by fluid phase gp340. The SpaP(I) polypeptide from S. mutans Ingbritt, which was C-terminally truncated by approximately 400 aa residues, did not bind gp340. Lactococci expressing AgI/II proteins, including SpaP(I), were aggregated by a synthetic 16 aa residue peptide SRCRP2 derived from the aa repeat block sequences within gp340. In coaggregation assays, SspB from S. gordonii was unique in mediating coaggregation with only group A and group E strains of Actinomyces naeslundii. All the other AgI/II polypeptides mediated coaggregation with group C and group D strains of A. naeslundii. Analysis of chimeric protein constructs revealed that coaggregation specificity was determined by sequences within the N-terminal half of AgI/II protein. A synthetic peptide (20 aa residues), which defines a putative adhesion epitope within the C-terminal region of polypeptide, inhibited AgI/II-mediated aggregation by gp340 but did not affect coaggregation with A. naeslundii. These results suggest that different mechanisms operate in interactions of AgI/II family polypeptides with native gp340, gp340 SRCR domain peptide, and A. naeslundii. Specificity of these interactions appears to be determined by discontinuous but interacting regions of the polypeptides, thus providing flexibility in receptor recognition for streptococcal colonization of the human host.
Assuntos
Adesinas Bacterianas/metabolismo , Antígenos de Bactérias/metabolismo , Aderência Bacteriana , Streptococcus/química , Adesinas Bacterianas/genética , Antígenos de Bactérias/genética , Humanos , Especificidade da Espécie , Streptococcus/metabolismoRESUMO
BACKGROUND: Carcinoma in pleomorphic salivary adenoma is a common histologic subtype of primary parotid malignancy. METHODS: In this study, 28 patients (predominantly male) with histologically diagnosed carcinoma in pleomorphic salivary adenoma presenting over 10 years were retrospectively reviewed. RESULTS: Only 25 percent of patients had a previously treated pleomorphic salivary adenoma. Although the presenting features suggested malignancy in some cases, overall they were nonspecific, overlapping with the presentation of benign disease. Preoperative investigations included fine needle aspiration cytology, which was only 29-percent sensitive, and computed tomography and/or magnetic resonance imaging. There were 14 superficial and 12 total or radical parotidectomies. The facial nerve was resected en bloc with the tumor in nine cases and immediately reconstructed with good reanimation results in patients with recent-onset facial paresis. Only 44 percent of patients had a complete histologic tumor clearance, and this was the most significant determinant of survival (p < 0.01, log-rank analysis). The locoregional control rate was 66 percent at 5 years, but recurrent disease proved invariably fatal. Five-year disease-specific survival was 44 percent with a high rate of disease-specific mortality (87 percent). CONCLUSIONS: Carcinoma in pleomorphic salivary adenoma is very difficult to diagnose preoperatively. Fine needle aspiration cytology had a disappointingly low sensitivity for this tumor, potentially misdirecting surgical management. While good locoregional disease control could be achieved with surgery and radiotherapy, carcinoma in pleomorphic salivary adenoma was shown to be aggressive with a high disease-specific rate of mortality. Given that incomplete tumor resection was the most important prognostic factor, a high index of clinical suspicion, radical ablative surgery, and immediate soft-tissue and nerve reconstruction for proven cases are advocated.
Assuntos
Adenoma Pleomorfo/cirurgia , Neoplasias Parotídeas/cirurgia , Adenoma Pleomorfo/diagnóstico , Adenoma Pleomorfo/epidemiologia , Adenoma Pleomorfo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina , Fracionamento da Dose de Radiação , Inglaterra/epidemiologia , Nervo Facial/cirurgia , Feminino , Humanos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Parotídeas/diagnóstico , Neoplasias Parotídeas/epidemiologia , Neoplasias Parotídeas/patologia , Prognóstico , Análise de SobrevidaRESUMO
Streptococcus gordonii colonizes multiple sites within the human oral cavity. This colonization depends upon the initial interactions of streptococcal adhesins with host receptors. The adhesins that bind salivary agglutinin glycoprotein (gp340) and human cell surface receptors include the antigen I/II (AgI/II) family polypeptides SspA and SspB and a sialic acid-binding surface protein designated Hsa or GspB. In this study we determined the relative functions of the AgI/II polypeptides and Hsa in interactions of S. gordonii DL1 (Challis) with host receptors. For an isogenic mutant with the sspA and sspB genes deleted the levels of adhesion to surface-immobilized gp340 were reduced 40%, while deletion of the hsa gene alone resulted in >80% inhibition of bacterial cell adhesion to gp340. Adhesion of S. gordonii DL1 cells to gp340 was sialidase sensitive, verifying that Hsa has a major role in mediating sialic acid-specific adhesion to gp340. Conversely, aggregation of S. gordonii cells by fluid-phase gp340 was not affected by deletion of hsa but was eliminated by deletion of the sspA and sspB genes. Deletion of the AgI/II polypeptide genes had no measurable effect on hsa mRNA levels or Hsa surface protein expression, and deletion of hsa did not affect AgI/II polypeptide expression. Further analysis of mutant phenotypes showed that the Hsa and AgI/II proteins mediated adhesion of S. gordonii DL1 to human HEp-2 epithelial cells. Hsa was also a principal streptococcal cell surface component promoting adhesion of human platelets to immobilized streptococci, but Hsa and AgI/II polypeptides acted in concert in mediating streptococcal cell-platelet aggregation. The results suggest that Hsa directs primary adhesion events for S. gordonii DL1 (Challis) with immobilized gp340, epithelial cells, and platelets. AgI/II polypeptides direct gp340-mediated aggregation, facilitate multimodal interactions necessary for platelet aggregation, and modulate S. gordonii-host engagements into biologically productive phenomena.
Assuntos
Adesinas Bacterianas/metabolismo , Aderência Bacteriana , Receptores de Superfície Celular/metabolismo , Streptococcus/patogenicidade , Adesinas Bacterianas/genética , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Aderência Bacteriana/genética , Aderência Bacteriana/fisiologia , Plaquetas/metabolismo , Plaquetas/microbiologia , Proteínas de Ligação ao Cálcio , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células Cultivadas , Proteínas de Ligação a DNA , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Deleção de Genes , Hemaglutininas Virais , Humanos , Mutação , Peptídeos/genética , Peptídeos/metabolismo , Fenótipo , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/metabolismo , Streptococcus/genética , Streptococcus/metabolismo , Proteínas Supressoras de TumorRESUMO
Guy's 13 is a mouse monoclonal antibody that specifically recognizes the major cell-surface adhesion protein SA I/II of Streptococcus mutans, one of the major causative agents of dental caries. Passive immunization with Guy's 13 prevents bacterial colonization in humans. To help elucidate the mechanism of prevention of colonization conferred by this antibody, the SA I/II epitope recognized by Guy's 13 was investigated. It was previously established that the epitope is conformational, being assembled from two non-contiguous regions of SA I/II. In the current study, using recombinant fragments of SA I/II and, ultimately, synthetic peptides, the discontinuous epitope was localized to residues 170-218 and 956-969. This work describes the mapping of a novel discontinuous epitope that requires an interaction between each determinant in order for epitope assembly and recognition by antibody to take place. Guy's 13 binds to the assembled epitope but not to these individual epitope fragments. The assembled epitope results from the interaction between the individual antigenic determinants and can be formed by mixing together determinants present on separate polypeptide chains. The data are consistent with one of the epitope fragments adopting a polyproline II-like helical conformation.