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1.
J Neurooncol ; 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38696050

RESUMO

PURPOSE: To benchmark palliative care practices in neurooncology centers across Germany, evaluating the variability in palliative care integration, timing, and involvement in tumor board discussions. This study aims to identify gaps in care and contribute to the discourse on optimal palliative care strategies. METHODS: A survey targeting both German Cancer Society-certified and non-certified university neurooncology centers was conducted to explore palliative care frameworks and practices for neurooncological patients. The survey included questions on palliative care department availability, involvement in tumor boards, timing of palliative care integration, and use of standardized screening tools for assessing palliative burden and psycho-oncological distress. RESULTS: Of 57 centers contacted, 46 responded (81% response rate). Results indicate a dedicated palliative care department in 76.1% of centers, with palliative specialists participating in tumor board discussions at 34.8% of centers. Variability was noted in the initiation of palliative care, with early integration at the diagnosis stage in only 30.4% of centers. The survey highlighted a significant lack of standardized spiritual care assessments and minimal use of advanced care planning. Discrepancies were observed in the documentation and treatment of palliative care symptoms and social complaints, underscoring the need for comprehensive care approaches. CONCLUSION: The study highlights a diverse landscape of palliative care provision within German neurooncology centers, underscoring the need for more standardized practices and early integration of palliative care. It suggests the necessity for standardized protocols and guidelines to enhance palliative care's quality and uniformity, ultimately improving patient-centered care in neurooncology.

2.
Sci Rep ; 14(1): 7761, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565603

RESUMO

Prognostic factors for overall survival (OS), percutaneous endoscopic gastrostomy (PEG) dependency, and long-term speech rehabilitation via voice prosthesis (VP) after laryngectomy for laryngeal or hypopharyngeal cancer were investigated in a retrospective population-based study in Thuringia, Germany. A total of 617 patients (68.7% larynx; hypopharynx; 31.3%; 93.7% men; median age 62 years; 66.0% stage IV) from 2001 to 2020 were included. Kaplan-Meier and Cox multivariable regression analyses were performed. 23.7% of patients received a PEG. 74.7% received a VP. Median OS was 131 months. Independent factors for lower OS were stage IV (compared to stage II; hazard ratio [HR] = 3.455; confidence interval [CI] 1.395-8.556) and laryngectomy for a recurrent disease (HR = 1.550; CI 1.078-2.228). Median time to PEG removal was 7 months. Prior partial surgery before laryngectomy showed a tendency for independent association for later PEG removal (HR = 1.959; CI 0.921-4.167). Postoperative aspiration needing treatment was an independent risk factor (HR = 2.679; CI 1.001-7.167) for later definitive VP removal. Laryngectomy continuously plays an important role in a curative daily routine treatment setting of advanced laryngeal or hypopharyngeal cancer in Germany. Long-term dependency on nutrition via PEG is an important issue, whereas use of VP is a stable long-term measure for voice rehabilitation.


Assuntos
Neoplasias Hipofaríngeas , Neoplasias Laríngeas , Laringe , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Laringectomia , Estudos Retrospectivos , Neoplasias Hipofaríngeas/cirurgia , Neoplasias Laríngeas/cirurgia , Laringe/cirurgia , Resultado do Tratamento
3.
Leuk Res ; 139: 107481, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38484432

RESUMO

The BYOND study evaluated the efficacy and safety of bosutinib 500 mg once daily in patients with chronic myeloid leukemia (CML) resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). These post-hoc analyses assessed the efficacy and safety of bosutinib by resistance or intolerance to prior TKIs (imatinib-resistant vs dasatinib/nilotinib-resistant vs TKI-intolerant), and cross-intolerance between bosutinib and prior TKIs (imatinib, dasatinib, nilotinib), in patients with Philadelphia chromosome-positive chronic phase CML. Data are reported after ≥3 years' follow-up. Of 156 patients with Philadelphia chromosome-positive chronic phase CML, 53 were imatinib-resistant, 29 dasatinib/nilotinib-resistant, and 74 intolerant to all prior TKIs; cumulative complete cytogenetic response rates at any time were 83.7%, 61.5%, and 86.8%, and cumulative major molecular response rates at any time were 72.9%, 40.7%, and 82.4%, respectively. Of 141, 95, and 79 patients who received prior imatinib, dasatinib, and nilotinib, 64 (45.4%), 71 (74.7%), and 60 (75.9%) discontinued the respective TKI due to intolerance; of these, 2 (3.1%), 5 (7.0%), and 0 had cross-intolerance with bosutinib. The response rates observed in TKI-resistant and TKI-intolerant patients, and low cross-intolerance between bosutinib and prior TKIs, further support bosutinib use for patients with Philadelphia chromosome-positive chronic phase CML resistant/intolerant to prior TKIs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02228382.


Assuntos
Compostos de Anilina , Antineoplásicos , Leucemia Mieloide de Fase Crônica , Nitrilas , Quinolinas , Humanos , Mesilato de Imatinib/efeitos adversos , Dasatinibe/efeitos adversos , Antineoplásicos/efeitos adversos , Cromossomo Filadélfia , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Resposta Patológica Completa
5.
Leukemia ; 38(5): 1072-1080, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38548962

RESUMO

Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.


Assuntos
Crise Blástica , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Sistema de Registros , Humanos , Crise Blástica/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Inibidores de Proteínas Quinases/uso terapêutico , Pessoa de Meia-Idade , Masculino , Adulto , Feminino , Idoso , Adulto Jovem , Transplante Homólogo , Europa (Continente) , Transplante de Células-Tronco Hematopoéticas/métodos , Prognóstico , Adolescente , Resultado do Tratamento , Taxa de Sobrevida , Gerenciamento Clínico , Seguimentos
6.
Cerebellum ; 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38363498

RESUMO

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

7.
Obes Sci Pract ; 10(1): e734, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38259353

RESUMO

Background: There are established links between the accumulation of body fat as visceral adipose tissue (VAT) and the risk of developing obesity-associated metabolic disease. Previous studies have suggested that levels of intake of specific foods and nutrients are associated with VAT accumulation after accounting for total energy intake. Objective: This study assessed associations between a priori selected dietary factors on VAT quantified using abdominal magnetic resonance imaging. Methods: The cross-sectional Multiethnic Cohort Adiposity Phenotype Study included n = 395 White, n = 274 Black, n = 269 Native Hawaiian, n = 425 Japanese American and n = 358 Latino participants (mean age = 69 years ± 3 SD). Participants were enrolled stratified on sex, race, ethnicity and body mass index. General linear models were used to estimate the mean VAT area (cm2) for participants categorized into quartiles based on their dietary intake of selected foods/nutrients adjusting for age, sex, racial and ethnic groups, the total percentage fat from whole-body dual energy X-ray absorptiometry and total energy. Results: There were significant inverse associations with VAT for dietary intake of total vegetables, total fruits (including juice), cereals, whole grains, calcium, copper and dietary fiber (p-trend ≤0.04). Positive trends were observed for VAT for participants who reported higher intake of potatoes, total fat and saturated fatty acids (SFA) (p-trend ≤0.02). Foods/nutrients that met the multiple testing significance threshold were total fruits, whole grains, copper, dietary fiber and SFA intake. Conclusions: These results highlight foods and nutrients including SFA, total fruit, whole grains, fiber and copper as potential candidates for future research to inform dietary guidelines for the prevention of chronic disease among older adults.

8.
eNeuro ; 11(2)2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38176906

RESUMO

Functional brain imaging studies in humans suggest involvement of the cerebellum in fear conditioning but do not allow conclusions about the functional significance. The main aim of the present study was to examine whether patients with cerebellar degeneration show impaired fear conditioning and whether this is accompanied by alterations in cerebellar cortical activations. To this end, a 2 d differential fear conditioning study was conducted in 20 cerebellar patients and 21 control subjects using a 7 tesla (7 T) MRI system. Fear acquisition and extinction training were performed on day 1, followed by recall on day 2. Cerebellar patients learned to differentiate between the CS+ and CS-. Acquisition and consolidation of learned fear, however, was slowed. Additionally, extinction learning appeared to be delayed. The fMRI signal was reduced in relation to the prediction of the aversive stimulus and altered in relation to its unexpected omission. Similarly, mice with cerebellar cortical degeneration (spinocerebellar ataxia type 6, SCA6) were able to learn the fear association, but retrieval of fear memory was reduced. In sum, cerebellar cortical degeneration led to mild abnormalities in the acquisition of learned fear responses in both humans and mice, particularly manifesting postacquisition training. Future research is warranted to investigate the basis of altered fMRI signals related to fear learning.


Assuntos
Mapeamento Encefálico , Condicionamento Clássico , Humanos , Animais , Camundongos , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Aprendizagem , Imageamento por Ressonância Magnética
9.
Leukemia ; 38(2): 235-249, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38238443

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome driven by pathologic activation of cytotoxic T-lymphocytes and macrophages. Despite advances in diagnostics and management, adult patients with lymphoma-associated HLH (LA-HLH) harbor particularly poor prognosis and optimal treatment remains challenging. As systematic data on LA-HLH are scarce, we aimed to synthesize research evidence by thorough analysis of the published literature in PubMed (MEDLINE-database) within the context of a scoping review. Of 595 search results, 132 articles providing information on 542 patients were reviewed and analyzed. Median patient age was 60 years (range, 18-98) with male predominance (62.7%). B- and T-NHL were equally represented (45.6% and 45.2%), Hodgkin's lymphoma was reported in 8.9% of the cases. The majority of patients (91.6%) presented in Ann-Arbor-Stages III and IV, and bone marrow infiltration was observed in a significant proportion of patients (61.5%). Soluble CD25 levels were markedly elevated (median 10,000 U/ml), with levels beyond 10,000 U/ml indicating unfavorable prognosis for 30-day and overall survival. 66.8% of the patients died after median 5.1 months. LA-HLH remains a clinical challenge requiring specialized management. Timely diagnosis and appropriate lymphoma-specific treatment are of utmost importance to enhance patient outcomes.


Assuntos
Linfo-Histiocitose Hemofagocítica , Linfoma , Adulto , Humanos , Masculino , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/patologia , Linfoma/complicações , Linfoma/diagnóstico , Prognóstico , Macrófagos/patologia , Medula Óssea/patologia
10.
Leukemia ; 38(1): 126-135, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38007586

RESUMO

In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3 years of follow-up in 156 patients with Philadelphia chromosome-positive chronic phase CML by age and Charlson Comorbidity Index scores (without the age component; mCCI) is reported. Cumulative major molecular response rates at any time on treatment were 73.6%, 64.5%, and 74.1% in patients <65, 65-74, and ≥75 years of age, and 77.9%, 63.0%, and 59.3% in patients with mCCI scores 2, 3, and ≥4, respectively. Patients <65, 65-74, and ≥75 years of age experienced grade 3/4 treatment-emergent adverse events (TEAEs) at rates of 74.7%, 78.8%, and 96.4% and permanent discontinuations due to AEs at rates of 22.1%, 39.4%, and 46.4%, respectively. In patients with mCCI 2, 3, and ≥4, respective rates of grade 3/4 TEAEs were 77.8%, 77.8%, and 86.7%, and permanent discontinuations due to AEs were 25.3%, 33.3%, and 43.3%. In conclusion, a substantial proportion of patients maintained/achieved cytogenetic and molecular responses across age groups and mCCI scores. Older patients (≥75 years) and those with high comorbidity burden (mCCI ≥4) may require more careful monitoring due to the increased risk of TEAEs. Clinicaltrials.gov: NCT02228382.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Quinolinas , Humanos , Idoso , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Nitrilas/efeitos adversos , Quinolinas/efeitos adversos , Comorbidade , Antineoplásicos/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do Tratamento
11.
Magn Reson Med ; 91(4): 1314-1322, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38044723

RESUMO

PURPOSE: To demonstrate J-difference coediting of glutamate using Hadamard encoding and reconstruction of Mescher-Garwood-edited spectroscopy (HERMES). METHODS: Density-matrix simulations of HERMES (TE 80 ms) and 1D J-resolved (TE 31-229 ms) of glutamate (Glu), glutamine (Gln), γ-aminobutyric acid (GABA), and glutathione (GSH) were performed. HERMES comprised four sub-experiments with editing pulses applied as follows: (A) 1.9/4.56 ppm simultaneously (ONGABA /ONGSH ); (B) 1.9 ppm only (ONGABA /OFFGSH ); (C) 4.56 ppm only (OFFGABA /ONGSH ); and (D) 7.5 ppm (OFFGABA /OFFGSH ). Phantom HERMES and 1D J-resolved experiments of Glu were performed. Finally, in vivo HERMES (20-ms editing pulses) and 1D J-resolved (TE 31-229 ms) experiments were performed on 137 participants using 3 T MRI scanners. LCModel was used for quantification. RESULTS: HERMES simulation and phantom experiments show a Glu-edited signal at 2.34 ppm in the Hadamard sum combination A+B+C+D with no overlapping Gln signal. The J-resolved simulations and phantom experiments show substantial TE modulation of the Glu and Gln signals across the TEs, whose average yields a well-resolved Glu signal closely matching the Glu-edited signal from the HERMES sum spectrum. In vivo quantification of Glu show that the two methods are highly correlated (p < 0.001) with a bias of ∼10%, along with similar between-subject coefficients of variation (HERMES/TE-averaged: ∼7.3%/∼6.9%). Other Hadamard combinations produce the expected GABA-edited (A+B-C-D) or GSH-edited (A-B+C-D) signal. CONCLUSION: HERMES simulation and phantom experiments show the separation of Glu from Gln. In vivo HERMES experiments yield Glu (without Gln), GABA, and GSH in a single MRS scan.


Assuntos
Ácido Glutâmico , Imageamento por Ressonância Magnética , Humanos , Espectroscopia de Ressonância Magnética/métodos , Glutamina , Glutationa/química , Ácido gama-Aminobutírico/química
12.
NeuroImmune Pharm Ther ; 2(4): 375-386, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38058999

RESUMO

Objectives: To evaluate whether prenatal tobacco exposure (PTE) is related to poorer cognitive performance, abnormal brain morphometry, and whether poor cognitive performance is mediated by PTE-related structural brain differences. Methods: The Adolescent Brain Cognitive Development study dataset was used to compare structural MRI data and neurocognitive (NIH Toolbox®) scores in 9-to-10-year-old children with (n=620) and without PTE (n=10,989). We also evaluated whether PTE effects on brain morphometry mediated PTE effects on neurocognitive scores. Group effects were evaluated using Linear Mixed Models, covaried for socio-demographics and prenatal exposures to alcohol and/or marijuana, and corrected for multiple comparisons using the false-discovery rate (FDR). Results: Compared to unexposed children, those with PTE had poorer performance (all p-values <0.05) on executive function, working memory, episodic memory, reading decoding, crystallized intelligence, fluid intelligence and overall cognition. Exposed children also had thinner parahippocampal gyri, smaller surface areas in the posterior-cingulate and pericalcarine cortices; the lingual and inferior parietal gyri, and smaller thalamic volumes (all p-values <0.001). Furthermore, among children with PTE, girls had smaller surface areas in the superior-frontal (interaction-FDR-p=0.01), precuneus (interaction-FDR-p=0.03) and postcentral gyri (interaction-FDR-p=0.02), while boys had smaller putamen volumes (interaction-FDR-p=0.02). Smaller surface areas across regions of the frontal and parietal lobes, and lower thalamic volumes, partially mediated the associations between PTE and poorer neurocognitive scores (p-values <0.001). Conclusions: Our findings suggest PTE may lead to poorer cognitive performance and abnormal brain morphometry, with sex-specific effects in some brain regions, in pre-adolescent children. The poor cognition in children with PTE may result from the smaller areas and subcortical brain volumes.

13.
Cancers (Basel) ; 15(21)2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37958431

RESUMO

The impact of the relation of human papillomavirus (HPV) and smoking status of oropharyngeal squamous cell carcinoma (OPSCC) on overall survival (OS) was investigated in a retrospective population-based study in Thuringia, Germany. A total of 498 patients with OPSCC (76.9% men; mean age 62.5 years) from 2018 to 2020 were included. OPSCC cases were 37.3% HPV-positive (+) (31.2% smokers; mean incidence: 2.91/100,000 population) and 57.8% HPV-negative (63.5% smokers; mean incidence: 4.50/100,000 population). Median follow-up was 20 months. HPV+ patients had significantly better OS than HPV-negative (-) patients (HPV+: 2-year OS: 90.9%; HPV-: 2-year OS: 73.6%; p < 0.001). In multivariable analysis, HPV- patients (hazard ratio (HR) = 4.5; 95% confidence interval (CI): 2.4-8.6), patients with higher N classification (N2: HR = 3.3; 95% CI: 1.71-6.20; N3: HR = 3.6; 95% CI: 1.75-7.31) and with a higher cancer staging (III: HR = 5.7; 95% CI: 1.8-17.6; IV: HR = 19.3; 95% CI: 6.3-57.3) had an increased hazard of death. HPV- smokers formed the majority in Thuringia. Nicotine and alcohol habits had no impact on OS. Optimizing OPSCC therapeutic strategies due to the dominance of HPV- is more important than discussing de-escalation strategies for HPV+ patients.

14.
Res Sq ; 2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-38014351

RESUMO

Background: Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Methods: Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Results: Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Conclusion: Our results (i) confirmed SCA6 being considered as a pure cerebellar gray matter disease, (ii) emphasise the involvement of cerebellar white matter in the neurophatology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

15.
Nat Commun ; 14(1): 6761, 2023 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-37875494

RESUMO

Cancer of unknown primary has a dismal prognosis, especially following failure of platinum-based chemotherapy. 10-20% of patients have a high tumor mutational burden (TMB), which predicts response to immunotherapy in many cancer types. In this prospective, non-randomized, open-label, multicenter Phase II trial (EudraCT 2018-004562-33; NCT04131621), patients relapsed or refractory after platinum-based chemotherapy received nivolumab and ipilimumab following TMBhigh vs. TMBlow stratification. Progression-free survival (PFS) represented the primary endpoint; overall survival (OS), response rates, duration of clinical benefit and safety were the secondary endpoints. The trial was prematurely terminated in March 2021 before reaching the preplanned sample size (n = 194). Among 31 evaluable patients, 16% had a high TMB ( > 12 mutations/Mb). Overall response rate was 16% (95% CI 6-34%), with 7.7% (95% CI 1-25%) vs. 60% (95% CI 15-95%) in TMBlow and TMBhigh, respectively. Although the primary endpoint was not met, high TMB was associated with better median PFS (18.3 vs. 2.4 months) and OS (18.3 vs. 3.6 months). Severe immune-related adverse events were reported in 29% of cases. Assessing on-treatment dynamics of circulating tumor DNA using combined targeted hotspot mutation and shallow whole genome sequencing as part of a predefined exploratory analysis identified patients benefiting from immunotherapy irrespective of initial radiologic response.


Assuntos
Neoplasias Pulmonares , Neoplasias Primárias Desconhecidas , Humanos , Nivolumabe/uso terapêutico , Ipilimumab/uso terapêutico , Neoplasias Primárias Desconhecidas/tratamento farmacológico , Neoplasias Primárias Desconhecidas/genética , Estudos Prospectivos , Neoplasias Pulmonares/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
16.
Biosensors (Basel) ; 13(10)2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37887101

RESUMO

In this paper, we propose a novel approach to utilize silicon nanowires as high-sensitivity pH sensors. Our approach works based on fixing the current bias of silicon nanowires Ion Sensitive Field Effect Transistors (ISFETs) and monitor the resulting drain voltage as the sensing signal. By fine tuning the injected current levels, we can optimize the sensing conditions according to different sensor requirements. This method proves to be highly suitable for real-time and continuous measurements of biomarkers in human biofluids. To validate our approach, we conducted experiments, with real human sera samples to simulate the composition of human interstitial fluid (ISF), using both the conventional top-gate approach and the optimized constant current method. We successfully demonstrated pH sensing within the physiopathological range of 6.5 to 8, achieving an exceptional level of accuracy in this complex matrix. Specifically, we obtained a maximum error as low as 0.92% (equivalent to 0.07 pH unit) using the constant-current method at the optimal current levels (1.71% for top-gate). Moreover, by utilizing different pools of human sera with varying total protein content, we demonstrated that the protein content among patients does not impact the sensors' performance in pH sensing. Furthermore, we tested real-human ISF samples collected from volunteers. The obtained accuracy in this scenario was also outstanding, with an error as low as 0.015 pH unit using the constant-current method and 0.178 pH unit in traditional top-gate configuration.


Assuntos
Técnicas Biossensoriais , Nanofios , Humanos , Transistores Eletrônicos , Silício/química , Nanofios/química , Líquido Extracelular , Técnicas Biossensoriais/métodos , Concentração de Íons de Hidrogênio
17.
Leukemia ; 37(11): 2150-2167, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37794101

RESUMO

From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers, sequential assessment of levels of residual disease and investigation of possible reasons for resistance, relapse or progression. Our scientific and clinical knowledge underpinning these requirements continues to evolve, as do laboratory methods and technologies. The European LeukemiaNet convened an expert panel to critically consider the current status of genetic laboratory approaches to help diagnose and manage CML patients. Our recommendations focus on current best practice and highlight the strengths and pitfalls of commonly used laboratory tests.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Recidiva
18.
Addiction ; 118(12): 2384-2396, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37563863

RESUMO

AIMS: Prior studies showed that methamphetamine (METH) users had greater than normal age-related brain atrophy; whether having the apolipoprotein E (APOE)-ε4 allele may be a contributory factor has not been evaluated. We aimed to determine the independent and combined effects of chronic heavy METH use and having at least one copy of the APOE-ε4 allele (APOE-ε4+) on brain morphometry and cognition, especially in relation to aging. METHODS: We compared brain morphometry and cognitive performance in 77 individuals with chronic heavy METH use (26 APOE-ε4+, 51 APOE-ε4-) and 226 Non-METH users (66 APOE-ε4+, 160 APOE-ε4-), using a 2 × 2 design (two-way analysis of co-variance). Vertex-wise cortical volumes, thickness and seven subcortical volumes, were automatically measured using FreeSurfer. Linear regression between regional brain measures, and cognitive scores that showed group differences were evaluated. Group differences in age-related decline in brain and cognitive measures were also explored. RESULTS: Regardless of APOE-ε4 genotype, METH users had lower Motor Z-scores (P = 0.005), thinner right lateral-orbitofrontal cortices (P < 0.001), smaller left pars-triangularis gyrus volumes (P = 0.004), but larger pallida, hippocampi and amygdalae (P = 0.004-0.006) than nonusers. Across groups, APOE-ε4+ METH users had the smallest volumes of superior frontal cortical gyri bilaterally, and of the smallest volume in left rostral-middle frontal gyri (all P-values <0.001). Smaller right superior-frontal gyrus predicted poorer motor function only in APOE-ε4+ participants (interaction-P < 0.001). Cortical volumes and thickness declined with age similarly across all participants; however, APOE-ε4-carriers showed thinner right inferior parietal cortices than noncarriers at younger age (interaction-P < 0.001). CONCLUSIONS: Chronic heavy use and having at least one copy of the APOE-ε4 allele may have synergistic effects on brain atrophy, particularly in frontal cortices, which may contribute to their poorer cognitive function. However, the enlarged subcortical volumes in METH users replicated prior studies, and are likely due to METH-mediated neuroinflammation.


Assuntos
Metanfetamina , Humanos , Alelos , Metanfetamina/efeitos adversos , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cognição , Genótipo , Apolipoproteína E4/genética , Atrofia/patologia , Testes Neuropsicológicos
19.
J Infect Dis ; 228(11): 1559-1570, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-37540098

RESUMO

BACKGROUND: The aim of this study was to determine whether neurometabolite abnormalities indicating neuroinflammation and neuronal injury are detectable in individuals post-coronavirus disease 2019 (COVID-19) with persistent neuropsychiatric symptoms. METHODS: All participants were studied with proton magnetic resonance spectroscopy at 3 T to assess neurometabolite concentrations (point-resolved spectroscopy, relaxation time/echo time = 3000/30 ms) in frontal white matter (FWM) and anterior cingulate cortex-gray matter (ACC-GM). Participants also completed the National Institutes of Health Toolbox cognition and motor batteries and selected modules from the Patient-Reported Outcomes Measurement Information System. RESULTS: Fifty-four participants were evaluated: 29 post-COVID-19 (mean ± SD age, 42.4 ± 12.3 years; approximately 8 months from COVID-19 diagnosis; 19 women) and 25 controls (age, 44.1 ± 12.3 years; 14 women). When compared with controls, the post-COVID-19 group had lower total N-acetyl compounds (tNAA; ACC-GM: -5.0%, P = .015; FWM: -4.4%, P = .13), FWM glutamate + glutamine (-9.5%, P = .001), and ACC-GM myo-inositol (-6.2%, P = .024). Additionally, only hospitalized patients post-COVID-19 showed age-related increases in myo-inositol, choline compounds, and total creatine (interaction P = .029 to <.001). Across all participants, lower FWM tNAA and higher ACC-GM myo-inositol predicted poorer performance on several cognitive measures (P = .001-.009), while lower ACC-GM tNAA predicted lower endurance on the 2-minute walk (P = .005). CONCLUSIONS: In participants post-COVID-19 with persistent neuropsychiatric symptoms, the lower-than-normal tNAA and glutamate + glutamine indicate neuronal injury, while the lower-than-normal myo-inositol reflects glial dysfunction, possibly related to mitochondrial dysfunction and oxidative stress in Post-COVID participants with persistent neuropsychiatric symptoms.


Assuntos
COVID-19 , Glutamina , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Espectroscopia de Prótons por Ressonância Magnética/métodos , Glutamina/metabolismo , Prótons , Teste para COVID-19 , COVID-19/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Inositol/metabolismo , Glutamatos/metabolismo , Ácido Aspártico/metabolismo
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