RESUMO
A common approach to interpreting spiking activity is based on identifying the firing fields-regions in physical or configuration spaces that elicit responses of neurons. Common examples include hippocampal place cells that fire at preferred locations in the navigated environment, head direction cells that fire at preferred orientations of the animal's head, view cells that respond to preferred spots in the visual field, etc. In all these cases, firing fields were discovered empirically, by trial and error. We argue that the existence and a number of properties of the firing fields can be established theoretically, through topological analyses of the neuronal spiking activity. In particular, we use Leray criterion powered by persistent homology theory, Eckhoff conditions and Region Connection Calculus to verify consistency of neuronal responses with a single coherent representation of space.
Assuntos
Hipocampo/fisiologia , Primatas/fisiologia , Percepção Espacial/fisiologia , Animais , Humanos , Modelos Teóricos , Neurônios/fisiologiaRESUMO
BACKGROUND: A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool. PATIENTS AND METHODS: This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured. RESULTS: Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%). CONCLUSION: In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests. CLINICAL TRIAL NUMBER: NCT02889978.
Assuntos
Detecção Precoce de Câncer , Neoplasias , Biomarcadores Tumorais/genética , Metilação de DNA , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Oncogenes , Estudos ProspectivosRESUMO
Salmonella enterica encodes a wide array of virulence factors. One novel virulence factor, an A2B5 toxin known as the typhoid toxin (TT), was recently identified among a variety of S. enterica serovars. While past studies have shown that some serovars encode both the TT (active subunits CdtB and PltA and binding subunit PltB) and a second binding subunit (ArtB), these serovars were thought to be the exception. Here, we show that genes encoding the TT are detected in more than 100 serovars representing distinct phylogenetic lineages of S. enterica subsp. enterica, although clade B and section Typhi are significantly more likely to encode TT genes than serovars from other clades. Furthermore, we show that 81% of these TT-positive serovars also encode artB, suggesting that the cooccurrence of both toxin binding subunits is considerably more common than previously thought. A combination of in silico modeling, bacterial two-hybrid system screening, and tandem affinity purification (TAP) of toxin subunits suggests that ArtB and PltB interact in vitro, at least under some growth conditions. While different growth conditions yielded slightly higher transcript abundances of artB and pltB, both genes had their highest relative transcript abundances when Salmonella was grown under low-Mg2+ conditions, suggesting that ArtB and PltB may compete for inclusion in the TT. Together, our results suggest that ArtB likely plays an important and previously underappreciated role in the biology of the TT produced by typhoidal and nontyphoidal SalmonellaIMPORTANCE While previous reports had suggested that the typhoid toxin (TT) could potentially use ArtB as an alternate binding subunit, this was thought to play a minor role in the evolution and biology of the toxin. In this study, we establish that both TT genes and artB are widespread among Salmonella enterica subsp. enterica, suggesting that TT likely plays a broader role in Salmonella virulence that extends beyond its proposed role in typhoid fever. Furthermore, our data suggest the selective maintenance of both toxin binding subunits, which may compete for inclusion in the holotoxin. Last, our data support the importance of characterizing diverse nontyphoidal Salmonella (NTS) serovars, as the presence of classically defined typhoidal virulence factors among NTS serovars continues to challenge the typhoid-nontyphoid Salmonella paradigm.
Assuntos
Endotoxinas/genética , Endotoxinas/metabolismo , Salmonella enterica/genética , Salmonella/genética , Sorogrupo , Linhagem Celular , Simulação por Computador , Humanos , Filogenia , Ligação Proteica , Salmonella/crescimento & desenvolvimento , Salmonella/patogenicidade , Salmonella enterica/classificação , Febre Tifoide/microbiologia , Virulência , Fatores de Virulência/metabolismoRESUMO
Background: : Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patients and methods: Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. Results: RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). Conclusions: In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant. ClinicalTrials.gov number: NCT01183780.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Mutação , Neovascularização Patológica , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas ras/genética , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Camptotecina/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Leucovorina/administração & dosagem , Masculino , Metástase Neoplásica , Prognóstico , Taxa de Sobrevida , RamucirumabRESUMO
Background: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results: Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5-15.6) versus 11.5 months (95% CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7-14.0) versus 13.1 months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration: NCT01183780.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/tratamento farmacológico , Fator D de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina/análogos & derivados , Método Duplo-Cego , Feminino , Fluoruracila , Humanos , Estimativa de Kaplan-Meier , Leucovorina , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/sangue , Intervalo Livre de Progressão , Receptores de Fatores de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , RamucirumabRESUMO
BACKGROUND: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION: NCT02187302 (NIH).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Padrão de Cuidado , Idoso , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Carcinoma de Células Renais/secundário , Ciclodextrinas/administração & dosagem , Feminino , Seguimentos , Humanos , Neoplasias Renais/patologia , Metástase Linfática , Masculino , Prognóstico , Taxa de SobrevidaRESUMO
Background: Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts. Patients and methods: Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS). Results: Among the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients. Conclusions: Cabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions. Trial registration number: NCT00940225.
Assuntos
Anilidas/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Neoplasias Hepáticas/tratamento farmacológico , Piridinas/administração & dosagem , Adulto , Idoso , Anilidas/efeitos adversos , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases , Piridinas/efeitos adversos , SorafenibeRESUMO
BACKGROUND: We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ). PATIENTS AND METHODS: Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure-response analysis was undertaken. RESULTS: Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69-1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure-response analysis indicated that patients with higher ramucirumab exposure had longer OS. CONCLUSION: The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population. CLINICALTRIALSGOV IDENTIFIER: NCT01246960.
Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Intervalo Livre de Doença , Método Duplo-Cego , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/efeitos dos fármacos , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Resultado do Tratamento , RamucirumabRESUMO
BACKGROUND: The RAISE phase III clinical trial demonstrated that ramucirumab + FOLFIRI improved overall survival (OS) [hazard ratio (HR) = 0.844, P = 0.0219] and progression-free survival (PFS) (HR = 0.793, P < 0.0005) compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Since some patient or disease characteristics could be associated with differential efficacy or safety, prespecified subgroup analyses were undertaken. This report focuses on three of the most relevant ones: KRAS status (wild-type versus mutant), age (<65 versus ≥65 years), and time to progression (TTP) on first-line therapy (<6 versus ≥6 months). PATIENTS AND METHODS: OS and PFS were evaluated by the Kaplan-Meier analysis, with HR determined by the Cox proportional hazards model. Treatment-by-subgroup interaction was tested to determine whether treatment effect was consistent between subgroup pairs. RESULTS: Patients with both wild-type and mutant KRAS benefited from ramucirumab + FOLFIRI treatment over placebo + FOLFIRI (interaction P = 0.526); although numerically, wild-type KRAS patients benefited more (wild-type KRAS: median OS = 14.4 versus 11.9 months, HR = 0.82, P = 0.049; mutant KRAS: median OS = 12.7 versus 11.3 months, HR = 0.89, P = 0.263). Patients with both longer and shorter first-line TTP benefited from ramucirumab (interaction P = 0.9434), although TTP <6 months was associated with poorer OS (TTP ≥6 months: median OS = 14.3 versus 12.5 months, HR = 0.86, P = 0.061; TTP <6 months: median OS = 10.4 versus 8.0 months, HR = 0.86, P = 0.276). The subgroups of patients ≥65 versus <65 years also derived a similar ramucirumab survival benefit (interaction P = 0.9521) (≥65 years: median OS = 13.8 versus 11.7 months, HR = 0.85, P = 0.156; <65 years: median OS = 13.1 versus 11.9 months, HR = 0.86, P = 0.098). The safety profile of ramucirumab + FOLFIRI was similar across subgroups. CONCLUSIONS: These analyses revealed similar efficacy and safety among patient subgroups with differing KRAS mutation status, longer or shorter first-line TTP, and age. Ramucirumab is a beneficial addition to second-line FOLFIRI treatment for a wide range of patients with mCRC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01183780.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Camptotecina/administração & dosagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , RamucirumabRESUMO
BACKGROUND: Docetaxel/cisplatin/infusional 5-fluorouracil (5-FU; DCF) is a standard chemotherapy regimen for patients with advanced gastric cancer (GC). This phase II study evaluated docetaxel/oxaliplatin (TE), docetaxel/oxaliplatin/5-FU (TEF), and docetaxel/oxaliplatin/capecitabine (TEX) in patients with advanced GC. PATIENTS AND METHODS: Patients with metastatic or locally recurrent gastric adenocarcinoma (including carcinoma of the gastro-oesophageal junction) were randomly assigned (1 : 1 : 1) to TE, TEF, or TEX. Each regimen was tested at two doses before full evaluation at optimized dose levels. The primary end point was progression-free survival (PFS). Overall survival (OS), tumour response, and safety were also assessed. A therapeutic index (median PFS relative to the incidence of febrile neutropenia) was calculated for each regimen and compared with DCF (historical data). RESULTS: Overall, 248 patients were randomly assigned to receive optimized dose treatment. Median PFS was longer with TEF (7.66 [95% confidence interval (CI): 6.97-9.40] months) versus TE (4.50 [3.68-5.32] months) and TEX (5.55 [4.30-6.37] months). Median OS was 14.59 (95% CI: 11.70-21.78) months for TEF versus 8.97 (7.79-10.87) months for TE and 11.30 (8.08-14.03) months for TEX. The rate of tumour response (complete or partial) was 46.6% (95% CI 35.9-57.5) for TEF versus 23.1% (14.3-34.0) for TE and 25.6% (16.6-36.4) for TEX. The frequency and type of adverse events (AEs) were similar across the three arms. Common grade 3/4 AEs were fatigue (21%), sensory neuropathy (14%), and diarrhoea (13%). Febrile neutropenia was reported in 2% (TEF), 14% (TE), and 9% (TEX) of patients. The therapeutic index was improved with TEF versus TEX, TE, or DCF. CONCLUSION: These results suggest that TEF is worthy of evaluation as an arm in a phase III trial or as a backbone regimen for new targeted agents in advanced GC. CLINICALTRIALS.GOV: Identifier Trial registration number: NCT00382720.
Assuntos
Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Compostos Organoplatínicos/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Taxoides/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Docetaxel , Esquema de Medicação , Feminino , Fluoruracila/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Estudos Prospectivos , Neoplasias Gástricas/mortalidade , Taxoides/efeitos adversos , Resultado do TratamentoRESUMO
AIMS: The Avastin(®) Registry - Investigation of Effectiveness and Safety (ARIES) observational cohort study (OCS) was designed to prospectively examine outcomes associated with bevacizumab-containing treatment for metastatic colorectal cancer (mCRC) in a community-based setting, where patient populations are less restricted than those in randomised trials. MATERIALS AND METHODS: Patients with mCRC who were eligible for bevacizumab in combination with chemotherapy in first- or second-line treatment were enrolled from November 2006 to September 2008. There were no protocol-specified treatment regimens; the dose and schedule of bevacizumab and chemotherapy were at the treating physician's discretion. The objectives in the ARIES OCS included analyses of progression-free survival (PFS), overall survival, treatment patterns and safety in each of the first- and second-line treatment cohorts. RESULTS: ARIES enrolled 1550 patients with mCRC receiving first-line therapy with bevacizumab. The median follow-up time was 20.6 months. The median PFS in this cohort was 10.2 months (95% confidence interval 9.8-10.6) and the median overall survival was 23.2 months (95% confidence interval 21.2-24.8). In a separate cohort of 482 patients with second-line mCRC, the median follow-up time was 16.9 months, the median PFS and overall survival from the start of second-line treatment to the end of follow-up was 7.9 months (95% confidence interval 7.2-8.3) and 17.8 months (95% confidence interval 16.5-20.7), respectively. Incidences of known bevacizumab-associated adverse events in ARIES were generally consistent with those previously reported in OCSs and randomised trials. CONCLUSION: Results from the prospective ARIES OCS add further evidence to support the effectiveness and safety of bevacizumab when added to first- and second-line treatment regimens for patients with mCRC in community treatment settings.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Estudos de Coortes , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Adulto JovemRESUMO
BACKGROUND: Targeted agents presently available for mutant KRAS metastatic colorectal cancer (mCRC) are bevacizumab and aflibercept. We evaluated the efficacy and safety of conatumumab (an agonistic monoclonal antibody against human death receptor 5) and ganitumab (a monoclonal antibody against the type 1 insulin-like growth factor receptor) combined with standard FOLFIRI chemotherapy as a second-line treatment in patients with mutant KRAS mCRC. PATIENTS AND METHODS: Patients with mutant KRAS metastatic adenocarcinoma of the colon or rectum refractory to fluoropyrimidine- and oxaliplatin-based chemotherapy were randomized 1 : 1 : 1 to receive intravenous FOLFIRI plus conatumumab 10 mg/kg (Arm A), ganitumab 12 mg/kg (Arm B), or placebo (Arm C) Q2W. The primary end point was progression-free survival (PFS). RESULTS: In total, 155 patients were randomized. Median PFS in Arms A, B, and C was 6.5 months (HR, 0.69; P = 0.147), 4.5 months (HR, 1.01; P = 0.998), and 4.6 months, respectively; median overall survival was 12.3 months (HR, 0.89; P = 0.650), 12.4 months (HR, 1.27; P = 0.357), and 12.0 months; and objective response rate was 14%, 8%, and 2%. The most common grade ≥3 adverse events in Arms A/B/C included neutropenia (30%/25%/18%) and diarrhea (18%/2%/10%). CONCLUSIONS: Conatumumab, but not ganitumab, plus FOLFIRI was associated with a trend toward improved PFS. Both combinations had acceptable toxicity.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adenocarcinoma/sangue , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/sangue , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/sangue , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Fluoruracila/administração & dosagem , Genótipo , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Irinotecano , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas p21(ras) , Receptores de IgG/genética , Resultado do TratamentoRESUMO
An increase in invasive Haemophilus influenzae type b (Hib) cases occurred in Minnesota in 2008 after the recommended deferral of the 12-15 months Hib vaccine boosters during a US vaccine shortage. Five invasive Hib cases (one death) occurred in children; four had incomplete Hib vaccination (three refused/delayed); one was immunodeficient. Subsequently, we evaluated Hib carriage and vaccination. From 18 clinics near Hib cases, children (aged 4 weeks-60 months) were surveyed for pharyngeal Hib carriage. Records were compared for Hib, diphtheria-tetanus-acellular pertussis (DTaP), and pneumococcal (PCV-7) vaccination. Parents completed questionnaires on carriage risk factors and vaccination beliefs. In 1631 children (February-March 2009), no Hib carriage was detected; Hib vaccination was less likely to be completed than DTaP and PCV-7. Non-type b H. influenzae, detected in 245 (15%) children, was associated with: male sex, age 24-60 months, daycare attendance >15 h/week, a household smoker, and Asian/Pacific Islander race/ethnicity. In 2009, invasive Hib disease occurred in two children caused by the same strain that circulated in 2008. Hib remains a risk for vulnerable/unvaccinated children, although Hib carriage is not widespread in young children.
Assuntos
Portador Sadio/epidemiologia , Infecções por Haemophilus/epidemiologia , Vacinas Anti-Haemophilus/administração & dosagem , Vacinas Anti-Haemophilus/imunologia , Haemophilus influenzae tipo b/isolamento & purificação , Vacinação/estatística & dados numéricos , Fatores Etários , Portador Sadio/microbiologia , Pré-Escolar , Etnicidade , Feminino , Infecções por Haemophilus/microbiologia , Infecções por Haemophilus/prevenção & controle , Humanos , Lactente , Masculino , Minnesota/epidemiologia , Faringe/microbiologia , Fatores de Risco , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
PURPOSE: (1) To evaluate the spectrum of BEST1 mutations within Australian Best Disease or vitelliform macular dystrophy (VMD) pedigrees, including any novel mutations; (2) to analyse the range of clinical presentations of this cohort; (3) to determine any possible genotype-phenotype correlations and (4) to compare clinical data of patients with phenotypic VMD, both with and without a BEST1 mutation. PATIENTS AND METHODS: Patients with suspected VMD were referred to clinical centres for ophthalmological assessment and genetic screening. When a mutation was identified in a proband, further family members were invited for clinical and genetic screening. RESULTS: We identified 42 patients with one of 13 BEST1 mutations. Seven mutations were novel. There were a further 14 probands in whom a BEST1 mutation was not identified. Median visual acuity in both VMD (mutation positive) and clinical VMD (no BEST1 mutation identified) groups reached driving standards (6/12 or better). CONCLUSION: We did not identify any firm genotype-phenotype correlations in our Australian VMD pedigrees, in which there was a spectrum of BEST1 mutations and marked variation in clinical presentation. Genetic screening remains the gold standard for VMD diagnosis. Patients should be counselled that visual acuity might remain at or above driving standards in at least one eye even in the presence of a BEST1 mutation.
Assuntos
Canais de Cloreto/genética , Proteínas do Olho/genética , Mutação/genética , Distrofia Macular Viteliforme/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Bestrofinas , Criança , Pré-Escolar , Percepção de Cores/fisiologia , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Retina/patologia , Acuidade Visual , Campos Visuais/fisiologia , Distrofia Macular Viteliforme/patologia , Distrofia Macular Viteliforme/fisiopatologia , Adulto JovemRESUMO
BACKGROUND/AIMS: Autosomal dominant optic atrophy (ADOA) is a genetically heterogenous disease. However, a large proportion of this disease is accounted for by mutations in OPA1. The aim of this longitudinal study was to investigate disease progression in Australian ADOA patients with confirmed OPA1 mutations. METHODS: Probands with characteristic clinical findings of ADOA were screened for OPA1 mutations, and relatives of identified mutation carriers were invited to participate. Disease progression was determined by sequential examination or using historical records over a mean of 9.6 (range 1-42) years. RESULTS: OPA1 mutation carriers (n = 158) were identified in 11 ADOA pedigrees. Sixty-nine mutation carriers were available for longitudinal follow-up. Using the right eye as the default, best-corrected visual acuity (BCVAR) remained unchanged (defined as visual acuity at or within one line of original measurement) in 43 patients (62%). BCVAR worsened by 2 lines in 13 patients (19%). BCVAR deteriorated by more than 2 lines in six patients (9%). Ten per cent of patients had an improvement in visual acuity. Mean time to follow-up was 9.6 years with the mean visual acuity being 6/18 for both the initial and subsequent measurements. There was no statistical significance in the rate of BCVAR loss across different OPA1 mutations (p = 0.55). CONCLUSION: OPA1-related ADOA generally progresses slowly and functional visual acuity is usually maintained. Longitudinal disease studies are important to enable appropriate counselling of patients. This study enables a better understanding of the natural history of ADOA.
Assuntos
GTP Fosfo-Hidrolases/genética , Atrofia Óptica Autossômica Dominante/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Criança , Progressão da Doença , Feminino , Variação Genética , Análise Heteroduplex/métodos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação/genética , Atrofia Óptica Autossômica Dominante/fisiopatologia , Disco Óptico/fisiopatologia , Linhagem , Polimorfismo Conformacional de Fita Simples/fisiologia , Acuidade VisualRESUMO
AIMS: To investigate the role of the common OPTN Met98Lys variant as a risk allele in open-angle glaucoma (OAG), autosomal dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON). METHODS: The presence of the Met98Lys variant was determined in a total of 498 (128 with normal-tension glaucoma (NTG)) patients with OAG, 29 patients who had myocilin-related OAG, 101 patients from ADOA pedigrees, 157 patients from LHON pedigrees and 218 examined OAG age-matched normal controls. RESULTS: 17 of 218 (7.8%) controls had the Met98Lys variant. 28 (5.6%) patients with OAG were Met98Lys positive. More Met98Lys carriers were found in the NTG group than in the high-tension glaucoma (HTG) group (p = 0.033). However, no significant difference was observed between the NTG and control cohorts (p = 0.609). Two MYOC mutation carriers were found to have the variant. The variant was found in 1 of 10 pedigrees with ADOA and in 8 of 35 pedigrees with LHON. CONCLUSION: Data from this study do not support a strong role for the OPTN Met98Lys variant in glaucoma, ADOA or LHON. However, a weak association was observed of the variant with NTG compared with that with HTG. Meta-analysis of all published data on the variant and glaucoma confirmed that the association, although weak, is highly statistically significant in the cohort with glaucoma versus controls.
Assuntos
Mutação , Doenças do Nervo Óptico/genética , Fator de Transcrição TFIIIA/genética , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Proteínas de Ciclo Celular , Distribuição de Qui-Quadrado , Criança , Análise Mutacional de DNA , DNA Mitocondrial/genética , Feminino , Frequência do Gene , Glaucoma de Ângulo Aberto/genética , Heterozigoto , Humanos , Masculino , Proteínas de Membrana Transportadoras , Atrofia Óptica Autossômica Dominante/genética , Atrofia Óptica Hereditária de Leber/genética , LinhagemRESUMO
AIMS: Multiple genetic causes of congenital cataract have been identified, both as a component of syndromes and in families that present with isolated congenital cataract. Linkage analysis was used to map the genetic locus in a six generation Australian family presenting with total congenital cataract. METHODS: Microsatellite markers located across all known autosomal dominant congenital cataract loci were genotyped in all recruited family members of the Tasmanian family. Both two point and multipoint linkage analysis were used to assess each locus under an autosomal dominant model. RESULTS: Significant linkage was detected at the telomere of the p arm of chromosome 1, with a maximum two point LOD of 4.21 at marker D1S507, a maximum multipoint exact LOD of 5.44, and an estimated location score of 5.61 at marker D1S507. Haplotype analysis places the gene inside a critical region between D1S228 and D1S199, a distance of approximately 6 megabases. The candidate gene PAX7 residing within the critical interval was excluded by direct sequencing in affected individuals. CONCLUSION: This is the third report of congenital cataract linkage to 1ptel. The critical region as defined by the shared haplotype in this family is clearly centromeric from the Volkmann cataract locus identified through study of a Danish family, indicating that two genes causing autosomal dominant congenital cataract map to the telomeric region of chromosome 1p.