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1.
J Am Chem Soc ; 146(13): 9224-9229, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38517326

RESUMO

Ligand-based functionalization strategies have emerged as powerful approaches to tune and optimize blue phosphorescence, which can involve nucleophilic addition to coordinated ligands or electrophilic functionalization via the coordination of exogenous Lewis acids. Whereas both have been used separately to enhance the photophysical properties of organometallic compounds with high-energy triplet states, in this work, we show that these two strategies can be used together on the same platform. Isocyanide-supported cyclometalated platinum compounds undergo nucleophilic addition with diethylamine to form a strong σ-donor acyclic diaminocarbene-supporting ligand. In a subsequent step, a cyanide ancillary ligand is converted into a more strongly π-acidic isocyanoborate via the coordination of a borane Lewis acid. Importantly, both of these ligand-based functionalization steps improve the quantum yields and lifetimes of the blue-phosphorescent complexes. This synergy results in complexes with photoluminescence quantum yields up to 0.40 for deep blue and 0.75 for sky blue regions and PL lifetimes on the order of 10-5 s.

2.
Front Neurol ; 14: 1227673, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37706007

RESUMO

Background: Systemic atherosclerosis and carotid intima-media thickness (IMT) have been widely used in clinical practice for ischemic stroke; however, little is known about the risk factors for unruptured intracranial aneurysms (UIAs) in patients with ischemic stroke (IS). Therefore, we performed this study to identify the risk factors and construct a prediction model for UIA in patients with IS. Methods: Data were retrospectively collected from patients with IS from 2015 to 2022 at the First Hospital of Quanzhou City, Quanzhou, Fujian, China. Risk factors for UIA in patients with IS were identified using a multivariate logistic regression model, and a receiver operating characteristic (ROC) curve was applied to construct the prediction model. Results: Out of the 122 patients with IS, 52 who presented with UIA (ISUIA) were categorized into the study group and the remaining 70 IS patients without UIA into the control group. Patients in the ISUIA group had lower carotid IMT and carotid artery plaque scores than those in the IS group (P < 0.05). Multivariate analyses found that aspirin use (OR: 12.987; P = 0.031), elevated C-reactive protein (CRP) level (OR: 1.019; P = 0.004), and carotid IMT > 0.09 mm (OR: 0.218; P < 0.001) were significantly associated with the risk of UIA in patients with IS. However, UIA in patients with IS was unaffected by the carotid artery plaque score (P = 0.114). The constricted prediction model based on the abovementioned factors for UIA in IS patients was 0.79 (95% CI: 0.71-0.87). Conclusion: The findings revealed that the risk factors for UIA in patients with IS included aspirin use, elevated CRP level, and smaller carotid IMT, and the predictive value of the prediction model was relatively better.

3.
Langmuir ; 39(23): 8091-8099, 2023 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-37267477

RESUMO

Increased gas adsorption in a series of post-synthetically modified metal-organic frameworks (MOFs) of the type HKUST-1 was achieved by the partial cation exchange process. Manipulation of post-synthetic conditions demonstrates high tunability in the site substitution and gas adsorption properties during the dynamic equilibrium process. In this work, post-synthetic modification of Cu3(BTC)2 is carried on by exposure to TM2+ solutions (TM = Mn, Fe, Co, Ni) at different time intervals. The crystal structure, composition, and morphology were studied by powder X-ray diffraction, Fourier-transform infrared spectroscopy, inductively coupled plasma optical emission spectroscopy, and scanning electron microscopy. Structural analysis supports the retention of the crystal structure and partial substitution of the Cu metal nodes within the framework. A linear increase in the transmetalation process is observed with Fe and Co with a maximum percentage of 39 and 18%, respectively. Conversely, relatively low cation exchange is observed with Mn having a maximum percentage of 2.40% and Ni with only 2.02%. Gas adsorption measurements and surface area analysis were determined for each species. Interestingly, (Cu/Mn)3(BTC)2 revealed the highest CO2 adsorption capacity of 5.47 mmol/g, compared to 3.08 mmol/g for Cu3(BTC)2. The overall increased gas adsorption can be attributed to the formation of defects in the crystal structure during the cation exchange process. These results demonstrate the outstanding potential of post-synthetic ion exchange as a general approach to fine-tuning the physical properties of existing MOF architectures.

4.
Clin Lung Cancer ; 24(1): e39-e49, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36376172

RESUMO

INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (ALK) rearrangements can be treated with ALK tyrosine kinase inhibitors. We assessed real-world ALK biomarker testing and treatment patterns of patients with NSCLC in the United States. PATIENTS AND METHODS: Data were extracted from the Flatiron Health electronic health record-derived deidentified database for patients aged ≥18 years with stage IIIB or IV NSCLC and ≥2 clinic visits between January 2011 and December 2019. RESULTS: Among 60,025 eligible patients, tumors from 36,691 (61.1%) patients were tested for ALK rearrangements, and 1042 (2.8%) tested positive (ALK+). From 2011 to 2019, ALK testing rates increased from 33.1% to 73.0%; testing via fluorescence in situ hybridization declined from 68.3% to 32.1% while next-generation sequencing increased from <1% to 52.2%. Although tissue samples were more commonly used than blood (85.1% vs. 13.5% of tests), blood sample testing increased from 0.1% in 2011 to 28.2% in 2019. Median (interquartile range) time from diagnosis of advanced NSCLC to first ALK+ test result was 23 (13-43) days, including laboratory processing time of 9 (6-14) days. For the 24.7% of patients with an ALK+ test result who began treatment before receiving the positive result, chemotherapy was initiated most often overall until 2018 when immuno-oncology agents became most common. CONCLUSION: Although ALK testing in NSCLC increased over time, testing rates among eligible patients did not reach 100% during the study period. Treatment decisions for some patients with NSCLC may have been made without important, guideline-recommended biomarker data.


Assuntos
Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Humanos , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/uso terapêutico
5.
J Oncol Pharm Pract ; 29(6): 1418-1427, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36131505

RESUMO

INTRODUCTION: This observational study describes the real-world economic burden in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) receiving a first-line ALK inhibitor, and the economic impact of brain metastases (BM). METHODS: Administrative claims data (Truven Health MarketScan® Commercial Claims and Encounters database and Medicare Supplemental and Coordination of Benefits database; January 1, 2015-March 31, 2020) for adult patients with ALK+ NSCLC who received a first-line ALK inhibitor were retrospectively reviewed. Healthcare costs and resource utilization were calculated on a per-patient-per-month (PPPM) basis and stratified by the presence or absence of BM prior to first-line ALK inhibitor. Factors associated with costs were identified. RESULTS: A total of 496 patients were eligible for analysis. Mean PPPM total healthcare costs were $21,961 for all patients receiving up to 1 year of a first-line ALK inhibitor. Patients were significantly more likely to have higher mean PPPM total costs if they had BM prior to first-line ALK inhibitor (vs. no BM; odds ratio: 1.11; 95% confidence interval: 1.02, 1.21; p = 0.013). Mean PPPM days of hospital stay (p = 0.0056), and inpatient hospital visits (p = 0.0030) were significantly higher for patients with BM compared to no BM. The main cost drivers for non-inpatient procedures for all patients were medications, radiation therapy, and other diagnostic procedures. CONCLUSIONS: The economic burden in patients with ALK+ NSCLC receiving a first-line ALK inhibitor was high. Patients with ALK+ NSCLC and BM had higher healthcare costs and resource utilization than patients without BM.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Humanos , Idoso , Estados Unidos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Quinase do Linfoma Anaplásico , Estudos Retrospectivos , Estresse Financeiro , Medicare , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário
6.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 45(6): 940-948, 2023 Dec 30.
Artigo em Chinês | MEDLINE | ID: mdl-38173105

RESUMO

Objective To compare the prevalence and disease burden of thyroid cancer and their trends between China and the globe from 1990 to 2019.Methods With the global disease burden data in 2019,Joinpoint was used to predict the trends of the disease burden of thyroid cancer in China and the globe from 1990 to 2019,and logarithmic linear model was used to test the predicted trends.The R language was used for predictive analysis and graphic plotting of the disease burden from 2020 to 2035.Results From 1990 to 2019,the standardized incidence rate and the standardized mortality rate of thyroid cancer in China were lower than those in the globe.The standardized incidence rate in China and the globe showed an increasing trend(with the increases of 102.65% and 40.65%,respectively),while the standardized mortality rate showed a decreasing trend(with the decreases of 7.63% and 4.91%,respectively).Compared with those of the female population,the standardized incidence and mortality rates of the Chinese male population increased significantly from 1990 to 2019(the rates of change in the male population were 48.65% and 214.60%,respectively;and the rates of change in the female population were -39.01% and 60.44%,respectively).China's overall standardized years of life lost(YLL),years lived with disability(YLD),and disability-adjusted life years(DALY)rates during the 30-year period were lower than the global average.The Chinese and global populations showed the standardized YLL rate decreasing by 16.61% and 6.88% and the standardized DALY rate decreasing by 10.77% and 3.65%,respectively,while the rates of standardized YLD increased by 128.91% and 46.89%,respectively.The magnitude of DALY in China and the world was mainly influenced by YLL.The standardized incidence,mortality,and DALY rates of the Chinese male population were gradually approaching the global levels.From 1990 and 2019,thyroid cancer showed a higher mortality rate in the population with the age ≥ 75 years and a higher incidence rate in the population with the age <75 years.It is projected that from 2020 to 2035,the standardized incidence rates in China and the world will increase by 36.66% and 21.15%,respectively;the standardized mortality rates will decrease by 20.19% and 3.46%,respectively;and the standardized DALY rate is expected to decrease by 7.08% in China and increase by 4.35% in the world.Conclusions From 1990 to 2019,China's standardized incidence rate of thyroid cancer increased and had a higher increase than the global level,and the standardized mortality rate decreased,with a slightly higher decrease than the global level.However,the increases in the standardized incidence rate and mortality rate of this disease in China's ≥75 years male population were severe.Although China's disease burden of thyroid cancer showed a decreasing trend in line with the global trend as a whole,the disease burden in the Chinese males was higher than that in the females.Specifically,the disease burden due to premature death was predominant,and the burden in specific populations requires policy attention.


Assuntos
Efeitos Psicossociais da Doença , Neoplasias da Glândula Tireoide , Masculino , Humanos , Feminino , Idoso , Anos de Vida Ajustados por Qualidade de Vida , Padrões de Referência , China/epidemiologia , Neoplasias da Glândula Tireoide/epidemiologia , Incidência
7.
J Blood Med ; 13: 517-524, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36188439

RESUMO

Background: US patients with hemophilia A can receive prophylaxis with extended half-life recombinant factor VIII (rFVIII) products, including efmoroctocog alfa (fragment crystallizable fusion protein) and rurioctocog alfa pegol (antihemophilic factor [recombinant], PEGylated). Objective: To evaluate dosing patterns and weekly consumption of extended half-life rFVIII products in the United States. Methods: We performed a retrospective analysis using the US Specialty Pharmacy Database (2015-2018). Included patients had a diagnosis of hemophilia A, ≥2 consecutive monthly claims for efmoroctocog alfa or rurioctocog alfa pegol for prophylaxis, and weight data. Outcome measures included weekly dosing frequency and dispensed weekly dose. Results: The analysis included 774 patients (efmoroctocog alfa, 506; rurioctocog alfa pegol, 268). Mean (SD) age was 24.2 (15.8) and 26.3 (14.9) years for patients receiving efmoroctocog alfa and rurioctocog alfa pegol, respectively; mean (SD) weight was 68.4 (36.8) and 79.8 (37.7) kg, respectively. The most frequent efmoroctocog alfa regimen was twice weekly (45.7%), followed by every 4 days (20.6%), every 3 days (9.1%), and 3 times per week (7.5%). The most frequent rurioctocog alfa pegol regimen was twice weekly (72.4%), followed by 3 times per week (8.7%), every 4 days (7.6%), and every 3 days (5.5%). The proportion of efmoroctocog alfa twice-weekly dispensing records increased from 31.5% to 50.9%, and every 4 days dispensing records decreased from 31.3% to 14.5% (2015-2018). The proportion of rurioctocog alfa pegol dispensing records remained broadly stable (2016-2018). Overall, mean (SD; median) weekly prophylactic dose was 105.4 (77.9; 92.6) IU/kg with efmoroctocog alfa, and 96.8 (41.9; 90.9) IU/kg with rurioctocog alfa pegol. Conclusion: In this database study, the most frequently observed dosing frequency was twice weekly for patients receiving efmoroctocog alfa or rurioctocog alfa pegol. The observed mean weekly consumption was slightly higher, and variation was greater, in patients receiving efmoroctocog alfa versus rurioctocog alfa pegol.

8.
Chem Sci ; 13(30): 8804-8812, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35975154

RESUMO

In this work we introduce a new series of ratiometric oxygen sensors based on phosphorescent cyclometalated iridium centers partnered with organic coumarin fluorophores. Three different cyclometalating ligands and two different pyridyl-containing coumarin types were used to prepare six target complexes with tunable excited-state energies. Three of the complexes display dual emission, with fluorescence arising from the coumarin ligand, and phosphorescence from either the cyclometalated iridium center or the coumarin. These dual-emitting complexes function as ratiometric oxygen sensors, with the phosphorescence quenched under O2 while fluorescence is unaffected. The use of blue-fluorescent coumarins results in good signal resolution between fluorescence and phosphorescence. Moreover, the sensitivity and dynamic range, measured with Stern-Volmer analysis, can be tuned two orders of magnitude by virtue of our ability to synthetically control the triplet excited-state ordering. The complex with cyclometalated iridium 3MLCT phosphorescence operates under hyperoxic conditions, whereas the two complexes with coumarin-centered phosphorescence are sensitive to very low levels of O2 and function as hypoxic sensors.

9.
Oncologist ; 27(9): 790-798, 2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-35781589

RESUMO

BACKGROUND: Real-world evidence for brigatinib, a next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) used in ALK-rearranged non-small cell lung cancer, is scarce. This retrospective study evaluated real-world brigatinib utilization in the US post other ALK-TKIs. MATERIALS AND METHODS: Adults with ≥1 brigatinib claim (index date) between 1 April 2017 and 30 September 2020 in the IQVIA longitudinal pharmacy claims database were followed until dose reduction, discontinuation, or end of follow-up. Patients had ≥12 months pre- and ≥1-month post-index observations. RESULTS: A total of 413 patients treated with brigatinib were analyzed. Over 80% received ≥1 prior ALK-TKI; alectinib and crizotinib were the most common (58.8% and 51.3% patients, respectively). The median follow-up was 8.4 months. The median time to treatment discontinuation (TTD) for brigatinib was 10.3 months (95% CI, 8.2-15.0), with 45% remaining on therapy at 12 months. The TTD was shortest (~8 months) in patients receiving both crizotinib and alectinib and longest in patients who received alectinib only prior to brigatinib (11.8 months). Adherence was high, with 92.7% of patients having a medication possession ratio of >80%. The mean dose compliance score was 1.0. Most patients reached the brigatinib dose of 180 mg/day (77%); 13.2% of patients had a dose reduction, with 89.3% and 84.6% continuing 180 mg/day therapy at 3 and 6 months, respectively. CONCLUSIONS: Brigatinib appears to be effective and well-tolerated in the real-world ALK+ NSCLC population in the US, showing benefit in patients after a next-generation ALK-TKI. Notably, dose reduction rates appeared markedly less than those seen in trials when most trial-related dose reductions were for asymptomatic laboratory abnormalities.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Crizotinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Compostos Organofosforados , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas , Estudos Retrospectivos , Estados Unidos
10.
Curr Med Res Opin ; 38(9): 1587-1593, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35815801

RESUMO

BACKGROUND: Second-generation anaplastic lymphoma kinase (ALK) gene targeted tyrosine kinase inhibitors (TKIs) alectinib and brigatinib have shown efficacy as front-line treatments for ALK-positive non-small cell lung cancer (NSCLC). No head-to-head data are currently available for brigatinib vs alectinib in the ALK-TKI-naive population. OBJECTIVE: To estimate the relative overall survival (OS) for brigatinib vs alectinib with indirect treatment comparisons (ITCs) using ALEX and ALTA-1L clinical trial data. METHODS: The latest aggregate data from the ALEX trial and final patient-level data from ALTA-1L were used. ITCs were conducted with/without treatment crossover adjustments to estimate relative OS. Bucher methods, anchored matching-adjusted indirect comparisons (MAICs) and unanchored MAICs were employed in ITCs without treatment crossover adjustments. An inverse probability of censoring weight Cox model, a marginal structure model and rank-preserving structural failure time models (with/without re-censoring) within an anchored MAIC were used in ITCs with treatment crossover adjustments. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. RESULTS: HRs for brigatinib vs alectinib for relative OS generated from ITCs without treatment crossover adjustments ranged from 0.90 (95% CI: 0.59-1.38) in the unanchored MAIC to 1.20 (95% CI: 0.69-2.11) using the Bucher method. Methods employing treatment switching adjustments estimated HRs for relative OS ranging from 0.74 (95% CI: 0.38-1.45) to 1.11 (95% CI: 0.63-1.94). Results from all ITCs did not indicate statistically different survival profiles. CONCLUSION: Regardless of ITC methodology, OS is comparable for brigatinib vs alectinib in patients with ALK+ NSCLC previously untreated with an ALK inhibitor.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Crizotinibe , Humanos , Compostos Organofosforados , Piperidinas , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas
11.
Clin Lung Cancer ; 23(6): 487-497, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35705448

RESUMO

BACKGROUND: NFE2L2 and/or KEAP1 mutations are associated with worse prognosis in all non-small cell lung cancer (NSCLC). We determined real-world survival outcomes and treatment patterns among patients with advanced squamous cell NSCLC by NFE2L2 and KEAP1 mutation status. PATIENTS AND METHODS: A retrospective study (January 2011-December 2018) was conducted using a de-identified US-based clinico-genomic database. Adult patients with advanced squamous cell NSCLC with ≥ 2 in-network visits and comprehensive genomic profiling during the study period were included. Outcomes included real-world progression free survival (rwPFS) by line of therapy and overall survival (OS). The real-world effectiveness of anti-PD-1/PD-L1 first-line therapy was also evaluated in patients with a NFE2L2 and/or KEAP1 mutation. RESULTS: Of 703 patients included (median age: 70.0 years), 31.6% had a NFE2L2 and/or KEAP1 mutation. The most common first- and second-line treatments regardless of mutation status were platinum-based chemotherapies and anti-PD-1/PD-L1 therapies. The most common third-line treatment was anti-PD-1/PD-L1 therapy in patients with a NFE2L2 and/or KEAP1 mutation and single-agent chemotherapy in patients with wild-type disease. Patients with a NFE2L2 and/or KEAP1 mutation versus wild-type disease had significantly shorter rwPFS (4.54 vs. 6.25 months; P = .003) following first- but not second- or third-line therapy and shorter median OS (13.59 vs. 17.37 months; P  =  .4105). No survival differences were observed in patients with a NFE2L2 and/or KEAP1 mutation receiving first-line anti-PD-1/PD-L1 therapies versus other therapies. CONCLUSIONS: Patients with advanced squamous cell NSCLC with a NFE2L2 and/or KEAP1 mutation have poor real-world survival, highlighting the need for a genotype-directed therapeutic strategy in this population.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Adulto , Idoso , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Células Epiteliais/metabolismo , Genômica , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/uso terapêutico , Estudos Retrospectivos
12.
Inorg Chem ; 61(22): 8498-8508, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35609301

RESUMO

We introduce phosphorescent platinum aryl acetylide complexes supported by tert-butyl-isocyanide and strongly σ-donating acyclic diaminocarbene (ADC) ligands. The precursor complexes cis-[Pt(CNtBu)2(C≡CAr)2] (4a-4f) are treated with diethylamine, which undergoes nucleophilic addition with one of the isocyanides to form the cis-[Pt(CNtBu)(ADC)(C≡CAr)2] complexes (5a-5f). The new compounds incorporate either electron-donating groups (4-OMe and 4-NMe2) or electron-withdrawing groups [3,5-(OMe)2, 3,5-(CF3)2, 4-CN, and 4-NO2] on the aryl acetylide. Experimental HOMO-LUMO gaps, estimated from cyclic voltammetry, span the range of 2.68-3.61 eV and are in most cases smaller than the unsubstituted parent complex, as corroborated by DFT. In the ADC complexes, peak photoluminescence wavelengths span the range of 428 nm (2a, unsubstituted phenylacetylide) to 525 nm (5f, 4-NO2-substituted), with the substituents inducing a red shift in all cases. The phosphorescence E0,0 values and electrochemical HOMO-LUMO gaps are loosely correlated, showing that both can be reduced by either electron-donating or electron-withdrawing substituents on the aryl acetylides. The photoluminescence quantum yields in the ADC complexes are between 0.044 and 0.31 and the lifetimes are between 4.8 and 14 µs, a factor of 1.8-10× higher (for ΦPL) and 1.2-3.6× longer (for τ) than the respective isocyanide precursor (ΦPL = 0.014-0.12, τ = 2.8-8.2 µs).

13.
Future Oncol ; 18(20): 2499-2510, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35608148

RESUMO

Aim: To conduct an indirect treatment comparison (ITC) of the relative efficacy of brigatinib and alectinib for progression-free survival in people with tyrosine kinase inhibitor (TKI)-naive ALK-positive non-small-cell lung cancer (NSCLC). Methods: Final aggregate and patient-level data from the ALTA-1L trial comparing brigatinib to crizotinib and published aggregate data from ALEX (comparing alectinib to crizotinib) were contrasted using Bucher ITC and matching-adjusted indirect comparisons (MAICs). Results: No statistically significant differences were identified between brigatinib and alectinib in reducing the risk of disease progression overall and in patients with baseline central nervous system metastases. Conclusion: Brigatinib appeared similar to alectinib in reducing risk of disease progression for people with TKI-naive ALK-positive NSCLC.


Patients with advanced non-small-cell lung cancer (NSCLC) who have a genetic marker called rearrangement in the anaplastic lymphoma kinase, or ALK-positive disease, are treated with targeted medications taken by mouth. Two medications, alectinib and brigatinib, are both considered first-line treatment for these patients but have not been compared head-to-head. Recently, updated clinical trial results were published for these medications. The present study utilized these updated results and advanced statistical tests to indirectly compare the effectiveness of the two treatments to help guide clinical treatment choices. Results showed brigatinib and alectinib have a similar magnitude of effect in decreasing the risk of a patient with ALK-positive NSCLC developing worsening disease.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico/genética , Carbazóis , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Ensaios Clínicos como Assunto , Crizotinibe , Progressão da Doença , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Compostos Organofosforados , Piperidinas , Inibidores de Proteínas Quinases , Pirimidinas
14.
JTO Clin Res Rep ; 3(3): 100285, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35199057

RESUMO

INTRODUCTION: EGFR exon 20 insertions (EGFRex20ins) are a diverse set of mutations in NSCLC that are refractory to tyrosine kinase inhibitors. We describe real-world EGFRex20ins detection patterns in patients with advanced NSCLC in the United States. METHODS: Data from 2011 to 2020 were extracted from the Flatiron Health electronic health record-derived deidentified database. RESULTS: Among 67,281 patients with advanced NSCLC and at least two clinic visits, 66.8% were tested for EGFR mutations, of whom 13.9% tested positive. Of these, 4.9% had EGFRex20ins. The median time from NSCLC diagnosis to the first positive EGFRex20ins test result was 23 days, including 9 days of laboratory testing time. The EGFRex20ins were reported in 0.6% to 1.0% of all patients with advanced NSCLC and account for 3.9% to 5.3% of all EGFR mutations. During the study period, reverse transcription-polymerase chain reaction testing rates decreased whereas next-generation sequencing rates increased both in overall and among patients with tumors positive for EGFRex20ins. Tissue was the most common sample type used for EGFR and EGFRexon20ins detection (81.1% and 84.9%, respectively), whereas blood sampling for EGFRexon20ins detection increased from 0% (2011) to 37.2% (2020). For 23.7% of patients with EGFRex20ins, treatment was initiated before receiving the first positive EGFRex20ins test result, with therapies including immuno-oncology agents as the most common treatment type from 2017 to 2020. CONCLUSIONS: EGFR testing and detection of EGFRex20ins in patients with NSCLC have increased slightly over time with the increasing use of next-generation sequencing. The current late-stage development of EGFRex20ins-targeted therapy is driving a need for more efficient testing.

15.
Orphanet J Rare Dis ; 16(1): 501, 2021 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-34863240

RESUMO

BACKGROUND: Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by cognitive impairment in most patients. This post hoc analysis evaluated changes in cognitive function, adaptive behavior and functional outcomes in patients with neuronopathic MPS II over time. Fifty-five children with MPS II were enrolled in a 24-month observational study (NCT01822184). The Differential Ability Scales, second edition (DAS-II; early years battery for ages 2 years 6 months to 6 years 11 months, school age battery for ages 7 years to 17 years 11 months), Vineland Adaptive Behavior Scales, second edition (VABS-II) and the Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) were performed at baseline and 3-month intervals over 2 years. A subgroup of 38 children with a DAS-II General Conceptual Ability (GCA) score of 55-85 (below average-very low abilities) at any time during the study were included in this analysis. RESULTS: Mean (standard deviation [SD]) early years DAS-II GCA score decreased from 73.4 (15.7, n = 22) at baseline to 62.7 (34.9, n = 6) at month 24. For the six patients with early years GCA assessments at baseline and month 24, mean (SD) GCA scores decreased from 72.3 (21.3) at baseline to 62.7 (34.9) at month 24. School age GCA scores were stable over 2 years: mean (SD) 72.4 (11.8, n = 10) at baseline; 74.3 (12.3, n = 8) at month 24. Mean (SD) VABS-II Adaptive Behavior Composite (ABC) scores were stable throughout the study (baseline, 81.8 [11.8, n = 36]; month 24, 81.0 [10.2, n = 13]). Some associations between items and domains of HS-FOCUS (p < 0.05) and DAS-II GCA and VABS-II ABC scores were shown, but there was no clear pattern of changes in HS-FOCUS over 2 years. CONCLUSIONS: The DAS-II measured changes in cognitive function over 2 years in younger patients with MPS II, whereas cognitive function in older patients remained stable. Further research is required to confirm the content validity of the DAS-II in different patient populations with MPS II. The VABS-II and HS-FOCUS were not sensitive tools for measuring behavioral and functional changes over 2 years. These findings may inform selection of appropriate cognitive and behavioral assessment tools for future studies.


Assuntos
Disfunção Cognitiva , Mucopolissacaridose II , Adaptação Psicológica , Idoso , Criança , Pré-Escolar , Cognição , Humanos
16.
J Blood Med ; 12: 699-708, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34393536

RESUMO

PURPOSE: To estimate the incremental economic burden of major surgeries in patients with von Willebrand disease (VWD). PATIENTS AND METHODS: This was a retrospective analysis of the IBM Health MarketScan® database (2008-2018). Patients with at least two healthcare visits for VWD in the database who had undergone at least one major surgery unrelated to VWD (identified via International Classification of Diseases, Ninth and Tenth Revisions procedure codes) were included. Patients without VWD with major surgeries were selected from a 1% random database sample. All patients had ≥12 months of continuous healthcare plan enrollment before and following their first major surgery. Patients with VWD were matched (1:1) with patients without VWD using propensity score matching. Regression models compared healthcare resource utilization and costs between the matched cohorts over a 12-month period after patients' index major surgery. RESULTS: After propensity score matching, 2972 pairs were selected. Musculoskeletal and digestive surgeries were the two most common major surgeries (patients with VWD, 39.6% and 25.0%; without VWD, 37.1% and 23.4%, respectively). Patients with VWD were significantly more likely (p<0.0001) to have an inpatient admission (odds ratio = 1.71; 95% confidence interval [CI] 1.52-1.92) or emergency room visit (odds ratio = 1.41; 95% CI 1.25-1.59) than patients without VWD. The numbers of inpatient admissions (incidence rate ratio [IRR] = 1.47; 95% CI 1.35-1.60), emergency room visits (IRR = 1.44; 95% CI 1.31-1.59), and outpatient visits (IRR = 1.16; 95% CI 1.11-1.21) per patient were also significantly greater for patients with VWD than for those without VWD (p<0.0001). Patients with VWD incurred significantly higher (p<0.0001) total healthcare costs (medical and pharmacy) per patient than patients without VWD ($50,733.89 versus $30,154.84, respectively). CONCLUSION: Healthcare resource utilization and associated costs among patients undergoing major surgeries were significantly higher for those with VWD than for patients without VWD.

17.
Ann Allergy Asthma Immunol ; 127(5): 568-574.e1, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34224864

RESUMO

BACKGROUND: The safety and efficacy of subcutaneous immune globulin 20% (human) solution (Cuvitru; Ig20Gly) for primary immunodeficiency disease (PID) have been demonstrated in 2 pivotal trials. OBJECTIVE: To describe patient characteristics and infusion parameters of patients with PID initiating Ig20Gly outside of a clinical trial setting. METHODS: This retrospective, observational study analyzed records of patients participating in the HelloCuvitru program, a patient support program in the United States providing Ig20Gly free of charge for the first 4 infusions to patients aged 2 years or older who had PID and no previous experience of Ig20Gly. Data were collected retrospectively from patient records and during nurse visits. RESULTS: A total of 817 patients (88% of 931 enrolled) completed 4 infusions. At the fourth Ig20Gly infusion, the median (interquartile range) dose was 0.55 (0.46-0.69) g/kg/mo, infusion rate per site was 40 (30.0-50.0) mL, and infusion rate per site was 47 (42.5-53.3) mL/h/site. By the fourth infusion, most patients (58%) received Ig20Gly at 2 infusion sites every 7 (30%) or 14 (25%) days. Median prescribed Ig20Gly dose per month was similar across age groups; median infusion volume per site increased with age. Most patients younger than 18 years received infusions every 14 days; patients aged 18 years or older were more likely to receive infusions weekly. Infusion parameters were similar regardless of whether patients received previous immunoglobulin subcutaneously or intravenously. CONCLUSION: In this large, real-world population of patients with PID, most Ig20Gly infusions were administered for less than 1 hour and required fewer than 2 infusion sites, consistent with the pivotal trials. Infusion rate per site was similar regardless of age, previous immunoglobulin treatment, or infusion frequency.


Assuntos
Transferência Adotiva/métodos , Imunoglobulinas Intravenosas/uso terapêutico , Doenças da Imunodeficiência Primária/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Imunoglobulinas Intravenosas/efeitos adversos , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
18.
J Manag Care Spec Pharm ; 27(2): 175-185, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33307935

RESUMO

BACKGROUND: von Willebrand disease (VWD) can lead to serious, life-threatening bleeding events associated with substantial clinical and economic burden. OBJECTIVE: To estimate the prevalence, health care resource utilization (HCRU), and costs associated with major bleeding events in patients with VWD. METHODS: This was a retrospective analysis of the IBM MarketScan database (2008-2016). Selected patients had ≥ 2 VWD diagnoses, no diagnosis of acquired coagulation factor deficiency, and continuous health care plan enrollment for ≥ 12 months from eligibility start date. Prevalence was calculated as the proportion of eligible patients with ≥ 1 major bleeding event during the observation period (start to end of continuous eligibility). HCRU and costs in the 12-month continuous enrollment period following the first major bleeding event were compared with those from a comparable 12-month period for patients without major bleeding events. RESULTS: Of the 19,785 patients with VWD, 15% experienced ≥ 1 major bleeding event during a median follow-up of 4 years; 89% of these events were gastrointestinal bleeds. For the economic analysis, 773 patients with ≥ 1 major bleeding event and 4,285 patients without major bleeding events met the selection criteria. Controlling for baseline covariates, patients with major bleeding events had significantly (P < 0.0001) more inpatient admissions (incidence rate ratio [IRR] = 3.2; 95% CI = 2.78-3.77), longer inpatient stays (IRR = 3.9; 95% CI = 3.12-4.93), and more emergency department visits (IRR = 2.0; 95% CI = 1.77-2.27) and outpatient visits (IRR = 1.3; 95% CI = 1.19-1.34) than patients without major bleeding events. Annual health care costs were significantly higher (P < 0.01) for patients with major bleeding events than those without them (predicted mean cost differences: total = $20,890, pharmacy = $2,593, and medical = $18,293). CONCLUSIONS: Major bleeding events were associated with increased HCRU and costs, mostly inpatient costs. Therefore, optimizing therapy to prevent or reduce major bleeding events has the potential to reduce health care use and costs in patients with VWD. DISCLOSURES: This study was funded by Baxalta U.S. Inc., a Takeda company (Lexington, MA). The study sponsor was involved with the study design, analysis, and interpretation of data; writing of the manuscript; and the decision to publish the article. Lu, Wu, and Ewenstein are employees of Baxalta U.S. Inc., a Takeda company, and are Takeda stock owners. Farahbakhshian is an employee of Shire U.S. Inc., a Takeda company, and is a Takeda stock owner. Oladapo was an employee of Baxalta U.S. Inc., a Takeda company, at the time the analysis was completed and the manuscript developed, and is a Takeda stock owner.


Assuntos
Efeitos Psicossociais da Doença , Custos de Cuidados de Saúde/estatística & dados numéricos , Hemorragia/economia , Doenças de von Willebrand/complicações , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Comércio/economia , Comércio/estatística & dados numéricos , Feminino , Seguimentos , Hemorragia/epidemiologia , Hemorragia/etiologia , Hemorragia/terapia , Humanos , Incidência , Lactente , Recém-Nascido , Seguro Saúde/economia , Seguro Saúde/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Admissão do Paciente/economia , Admissão do Paciente/estatística & dados numéricos , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto Jovem , Doenças de von Willebrand/economia , Doenças de von Willebrand/terapia
19.
Cancer Biomark ; 30(2): 179-191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33104022

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor with a high mortality rate. Aberrant activation of signal transducers and activators of transcription (STAT) signaling results in tumor pathogenesis and progression by regulating cell cycle, cell survival and immune response. METHODS: Therapeutic targets and prognostic biomarkers within the STAT family in GBM were explored using web applications and databases. RESULTS: High levels of STAT1/3/5A/5B/6 and low levels of STAT4 were observed in GBM patients. GBM patients expressing high STAT1/2/3/5A/6 and low STAT4/5B levels had the worse overall survival. Among the STAT family, STAT4 and STAT6 were the most frequently mutated genes. A low to moderate correlation among members of the STAT family was observed. Additionally, the STATs were involved in activation or inhibition of cancer related pathways. Analysis of immune infiltrates showed STAT5A levels to be significantly correlated with abundance of immune cells and levels of immune gene biomarkers. Gene ontology (GO) functions and KEGG pathway analysis indicated that STAT5A is involved in immune response-regulating signaling pathway, neutrophil and lymphocyte mediated immunity, single-stranded DNA binding, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, NF-kappa B signaling pathway and TNF signaling pathway. Moreover, several kinase and transcription factor targets of STAT5A in GBM were identified. CONCLUSION: We report here therapeutic targets, prognostic biomarkers and regulation network of STAT family in GBM. These findings lay a foundation for further studies on the role of STAT family in therapy and prognosis of GBM. Further studies are required to verify our results.


Assuntos
Bases de Dados Factuais/normas , Glioblastoma/genética , Fatores de Transcrição STAT/metabolismo , Glioblastoma/patologia , Humanos , Prognóstico , Transdução de Sinais
20.
Life Sci ; 261: 118486, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32976881

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most common subtype of brain cancer, encompassing 16% of all primary brain cancers. The prognosis of GBM is poor, with a 5-year-survial of approximately 5%. Increasing evidence has revealed that chemokines in the tumor microenvironment (TME) are often altered, thus affecting tumor proliferation and metastasis. METHOD: Multi-omics and bioinformatics tools were utilized to clarify the role of CXC chemokine in GBM. RESULT: Most CXC chemokines were found to be differentially regulated in GBM, which correlated with patient prognosis. CXC chemokines were found to activate cancer-related signaling pathways, thus affecting immune infiltration. Interestingly, this was found to be associated with drug resistance. Most CXC chemokines were significantly correlated with abundance of B cells, CD8+ cells and dendritic cells. Furthermore, somatic copy number alterations of CXC chemokines can inhibit dendritic cell infiltration. Moreover, CXCL1 was selected as a hub gene, and several kinase, miRNA and transcription factor targets of CXCL1 were identified. CONCLUSION: our study provides novel insights into CXC chemokine expression and their role in the GBM microenvironment. These results are able to provide more data about prognostic biomarkers and therapeutic targets of GBM.


Assuntos
Neoplasias Encefálicas/genética , Quimiocinas CXC/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Neoplasias Encefálicas/diagnóstico , Redes Reguladoras de Genes , Glioblastoma/diagnóstico , Humanos , Prognóstico , Microambiente Tumoral
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