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1.
Orthopedics ; : 1-6, 2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39312743

RESUMO

BACKGROUND: Lumbar spine fractures are common injuries associated with substantial morbidity for patients and socioeconomic burden. This study sought to epidemiologically analyze lumbar spine fractures by mechanism of injury and identify temporal trends in patient demographics and disposition, which few studies have previously evaluated. MATERIALS AND METHODS: A retrospective analysis was done of the US National Electronic Injury Surveillance System (NEISS) database between 2003 and 2022. The sample contained all patients 2 to 101 years old with product-related lumbar fractures presenting to participating institutions' emergency departments. A total of 15,196 unweighted injuries (642,979 weighted injuries) were recorded. RESULTS: Overall, there was a 20-year incidence rate of 10.14 cases per 100,000 person-years with a 2-fold increase in fracture incidence. Females were more prone to lumbar fracture than males (P=.032). Injuries primarily stemmed from a fall (76.6%). The incidence of lumbar fracture increased most significantly in older patients, with patients 80 years and older showing the greatest annual increase (ß=8.771, R2=0.7439, P<.001) and patients 60 to 69 years showing the greatest percent increase with a 3.24-fold increase in incidence. Most (58.9%) of the fractures occurred at home. Females were more often injured at home compared with males (P<.001), who more often sustained lumbar fractures during recreational or athletic activity (P<.001). All patients older than 40 years showed at least a doubling in incidence rate of lumbar fracture between 2003 and 2022. CONCLUSION: These data demonstrate the pressing need to address poor bone health in the aging population, shown here to have an increasing fracture burden. [Orthopedics. 202x;4x(x):xx-xx.].

4.
Spine Deform ; 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39331321

RESUMO

STUDY DESIGN: Retrospective cohort study. PURPOSE: The impact of neuromuscular disorders such as multiple sclerosis (MS) on outcomes following long segment fusion is underreported. This study evaluates the impact of MS on two-year (2Y) postoperative complications and revisions following ≥ 4-level fusion for adult spinal deformity (ASD). METHODS: Patients undergoing ≥ 4-level fusion for ASD were identified from a statewide database. Patients with a baseline diagnosis of MS were also identified. Patients with infectious/traumatic/neoplastic indications were excluded. Subjects were 1:1 propensity score-matched (MS to no-MS) based on age, sex and race and compared for rates of 2Y postoperative complications and reoperations. Logistic regression models were utilized to determine risk factors for adverse outcomes at 2Y. RESULTS: 86 patients were included overall (n = 43 per group). Age, sex, and race were comparable between groups (p > 0.05). MS patients incurred higher charges for their surgical visit ($125,906 vs. $84,006, p = 0.007) with similar LOS (8.1 vs. 5.3 days, p > 0.05). MS patients experienced comparable rates of overall medical complications (30.1% vs. 25.6%) and surgical complications (34.9% vs. 30.2%); p > 0.05. MS patients had similar rates of 2Y revisions (16.3% vs. 9.3%, p = 0.333). MS was not associated with medical, surgical, or overall complications or revisions at minimum 2Y follow-up. CONCLUSION: Patients with MS experienced similar postoperative course compared to those without MS following ≥ 4-level fusion for ASD. This data supports the findings of multiple previously published case series' that long segment fusions for ASD can be performed relatively safely in patients with MS.

5.
Front Radiol ; 4: 1327406, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39175870

RESUMO

Background: Cardiac magnetic resonance is a useful clinical tool to identify late gadolinium enhancement in heart failure patients with implantable electronic devices. Identification of LGE in patients with CIED is limited by artifact, which can be improved with a wide band radiofrequency pulse sequence. Objective: The authors hypothesize that image quality of LGE images produced using wide-band pulse sequence in patients with devices is comparable to image quality produced using standard LGE sequences in patients without devices. Methods: Two independent readers reviewed LGE images of 16 patients with CIED and 7 patients without intracardiac devices to assess for image quality, device-related artifact, and presence of LGE using the American Society of Echocardiography/American Heart Association 17 segment model of the heart on a 4-point Likert scale. The mean and standard deviation for image quality and artifact rating were determined. Inter-observer reliability was determined by calculating Cohen's kappa coefficient. Statistical significance was determined by T-test as a p {less than or equal to} 0.05 with a 95% confidence interval. Results: All patients underwent CMR without any adverse events. Overall IQ of WB LGE images was significantly better in patients with devices compared to standard LGE in patients without devices (p = 0.001) with reduction in overall artifact rating (p = 0.05). Conclusion: Our study suggests wide-band pulse sequence for LGE can be applied safely to heart failure patients with devices in detection of LV myocardial scar while maintaining image quality, reducing artifact, and following routine imaging protocol after intravenous gadolinium contrast administration.

6.
JAMA Netw Open ; 7(7): e2422674, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-39052293

RESUMO

Importance: Immuno-oncology agents have changed the treatment paradigm for metastatic renal cell carcinoma (mRCC). Such therapies improve survival but can impose considerable health care resource use (HCRU) and associated costs, necessitating their examination. Objective: To compare HCRU, costs, and clinical outcomes among patients receiving first-line pembrolizumab plus axitinib (P+A) or ipilimumab plus nivolumab (I+N). Design, Setting, and Participants: This retrospective cohort study used data from an administrative claims database on patients with mRCC receiving first-line P+A or I+N that was initiated between January 2018 and May 2020. Data were analyzed from February 2021 to July 2022. Exposure: First-line P+A or I+N. Main Outcome and Measures: HCRU and costs during the first 90 days, full first-line treatment, and full follow-up periods were assessed. Using Kaplan-Meier analysis, time on treatment, overall survival, time to first emergency department (ED) visit, and time to first inpatient stay were compared. Results: Among 507 patients, there were 126 patients receiving P+A (91 male [72.2%]; mean [SD] age, 67.93 [9.66] y) and 381 patients receiving I+N (271 male [71.1%]; mean [SD] age, 66.52 [9.94] years). The median time on treatment was longer for the P+A compared with I+N group (12.4 months [95% CI, 8.40 months to not estimable] vs 4.1 months [95% CI, 3.07 to 5.30 months]; P < .001). The median time to first ED visit was longer for the P+A than I+N group (7.2 months [95% CI 3.9 to 11.1 months ] vs 3.3 months [95% CI, 2.6 to 3.9 months]; P = .005), as was time to first inpatient stay (9.0 months [95% CI 6.5 months to not estimable] vs 5.6 months [95% CI, 3.9 to 7.9 months]; P = .02). During the first 90 days, a lower proportion of the P+A than N+I group had ED visits (43 patients [34.1%] vs 182 patients [47.8%] and inpatient stays (24 patients [19.1%) vs144 patients [37.8%]; P < .001). During full follow-up, mean total adjusted costs were similar for P+A and I+N groups, but adjusted 12-month estimated total costs were higher for P+A than I+N groups ($325 574 vs $ 263 803; P = .03). Conclusions and Relevance: In this study, treatment with P+A was associated with longer time on treatment, time to first ED visit, and inpatient stay, while 12-month estimated costs were higher for the P+A group. This is among the first clinical studies to evaluate economic burden associated with modern treatments for mRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Nivolumabe , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Masculino , Feminino , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Nivolumabe/uso terapêutico , Nivolumabe/economia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/economia , Axitinibe/uso terapêutico , Ipilimumab/uso terapêutico , Recursos em Saúde/estatística & dados numéricos , Recursos em Saúde/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Custos de Cuidados de Saúde/estatística & dados numéricos
8.
Artigo em Inglês | MEDLINE | ID: mdl-39017523

RESUMO

BACKGROUND: Vertebral fractures are associated with enduring back pain, diminished quality of life, as well as increased morbidity and mortality. Existing epidemiological data for cervical and thoracic vertebral fractures are limited by insufficiently powered studies and a failure to evaluate the mechanism of injury. QUESTION/PURPOSE: What are the temporal trends in incidence, patient characteristics, and injury mechanisms of cervical and thoracic vertebral fractures in the United States from 2003 to 2021? METHODS: The United States National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP) database collects data on all nonfatal injuries treated in US hospital emergency departments and is well suited to capture epidemiological trends in vertebral fractures. As such, the NEISS-AIP was queried from 2003 to 2021 for cervical and thoracic fractures. The initial search by upper trunk fractures yielded 156,669 injuries; 6% (9900) of injuries, with a weighted frequency of 638,999 patients, met the inclusion criteria. The mean age was 62 ± 25 years and 52% (334,746 of 638,999) of patients were females. Descriptive statistics were obtained. Segmented regression analysis, accounting for the year before or after 2019 when the NEISS sampling methodology was changed, was performed to assess yearly injury trends. Multivariable logistic regression models with age and sex as covariates were performed to predict injury location, mechanism, and disposition. RESULTS: The incidence of cervical and thoracic fractures increased from 2.0 (95% CI 1.4 to 2.7) and 3.6 (95% CI 2.4 to 4.7) per 10,000 person-years in 2003 to 14.5 (95% CI 10.9 to 18.2) and 19.9 (95% CI 14.5 to 25.3) in 2021, respectively. Incidence rates of cervical and thoracic fractures increased for all age groups from 2003 to 2021, with peak incidence and the highest rate of change in individuals 80 years or older. Most injuries occurred at home (median 69%), which were more likely to impact older individuals (median [range] age 75 [2 to 106] years) and females (median 61% of home injuries); injuries at recreation/sports facilities impacted younger individuals (median 32 [3 to 96] years) and male patients (median 76% of sports facility injuries). Falls were the most common injury mechanism across all years, with females more likely to be impacted than males. The proportion of admissions increased from 33% in 2003 to 50% in 2021, while the proportion of treated and released patients decreased from 53% to 35% in the same period. CONCLUSION: This epidemiological study identified a disproportionate increase in cervical and thoracic fracture incidence rates in patients older than 50 years from 2003 to 2021. Furthermore, high hospital admission rates were also noted resulting from these fractures. These findings indicate that current osteoporosis screening guidelines may be insufficient to capture the true population at risk of osteoporotic fractures, and they highlight the need to initiate screening at an earlier age. LEVEL OF EVIDENCE: Level III, prognostic study.

9.
Semin Perinatol ; 48(4): 151921, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38871489

RESUMO

The maternal/newborn dyad presents special challenges to infection management. Early in the COVID-19 pandemic, lack of information regarding SARS-CoV-2 transmission and virulence made it difficult to develop appropriate care guidance when pregnant persons had COVID-19 at the time of presentation for childbirth. We will review the considerations for the parturient, newborn, and care team, and describe the evolution of perinatal COVID management guidance.


Assuntos
COVID-19 , Transmissão Vertical de Doenças Infecciosas , Assistência Perinatal , Complicações Infecciosas na Gravidez , SARS-CoV-2 , Humanos , COVID-19/terapia , COVID-19/transmissão , COVID-19/prevenção & controle , Recém-Nascido , Gravidez , Feminino , Complicações Infecciosas na Gravidez/terapia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Assistência Perinatal/métodos
10.
J Med Chem ; 67(12): 9776-9788, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38837951

RESUMO

Type II kinase inhibitors bind in the "DFG-out" kinase conformation and are generally considered to be more potent and selective than type I inhibitors, which target a DFG-in conformation. Nine type II inhibitors are currently clinically approved, with more undergoing clinical development. Resistance-conferring secondary mutations emerged with the first series of type II inhibitors, most commonly at residues within the kinase activation loop and at the "gatekeeper" position. Recently, new inhibitors have been developed to overcome such mutations; however, mutations activating other pathways (and/or other targets) have subsequently emerged on occasion. Here, we systematically summarize the secondary mutations that confer resistance to type II inhibitors, the structural basis for resistance, newer inhibitors designed to overcome resistance, as well as the challenges and opportunities for the development of new inhibitors to overcome secondary kinase domain mutations.


Assuntos
Mutação , Inibidores de Proteínas Quinases , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Humanos , Animais
11.
Cancers (Basel) ; 16(12)2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38927928

RESUMO

Regulatory approval of immune checkpoint inhibitors (ICIs) was based on results of large, randomized clinical trials, resulting in limited outcomes data in patient cohorts typically underrepresented in such trials. The objective of this study was to evaluate the efficacy and safety of ICIs in these unique patient cohorts. This is a multicenter, retrospective analysis of real-world data at six academic and community clinics in the United States from 1 January 2011 to 1 April 2018. Patients were included if they had received at least one cycle of ICI treatment. Unique patient cohorts included age > 75 years, non-White race, positive smoking history, ECOG performance status (PS) ≥ 2, BMI ≥ 30 kg/m2, autoimmune diseases (AIDs), chronic viral infections (CVI), extensive prior lines of therapy (LOTs), or >three metastatic sites. Immune-related adverse events (irAEs), overall survival (OS), and time to treatment failure were evaluated in the entire cohort and in NSCLC patients treated with PD-(L)1 monotherapy. Outcomes and their association with unique patient cohorts were compared on univariate analysis and multivariate analysis to those without a particular characteristic in the entire NSCLC PD-(L)1 monotherapy cohorts. In total, 1453 patients were included: 56.5%-smokers, 30.4%-non-White, 22.8%-elderly, 20.8%-ECOG PS ≥ 2, 15.7%-history of AIDs, and 4.7%-history of CVI. The common ICIs were nivolumab (37.1%) and pembrolizumab (22.2%). Black patients, compared to White patients, experienced fewer irAEs (OR 0.54, p < 0.001). An ECOG PS of ≥2 (HR = 2.01, p < 0.001) and an increased number of previous LOTs were associated with poor OS (the median OS of 26.2 vs. 16.2 vs. 9.6 months for one vs. two vs. three prior LOTs, p < 0.001). The above results were confirmed in anti-PD-(L)1 monotherapy non-small cell lung cancer patients (n = 384). Overall, ICIs were safe and efficacious in these typically underrepresented patient cohorts. We noted ECOG PS ≥ 2 and an increased prior LOTs were associated with poor ICI efficacy, and Black patients, compared to White patients, experienced fewer irAEs.

12.
Nutrients ; 16(11)2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38892497

RESUMO

Many guidelines have been published to help diagnose food allergies, which have included feeding difficulties as a presenting symptom (particularly for non-IgE-mediated gastrointestinal allergies). This study aimed to investigate the prevalence of feeding difficulties in children with non-IgE-mediated gastrointestinal allergies and the association of such difficulties with symptoms and food elimination. An observational study was performed at Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Children aged 4 weeks to 16 years without non-allergic co-morbidities who improved on an elimination diet using a previously published Likert scale symptom score were included. This study recruited 131 children, and 114 (87%) parents completed the questionnaire on feeding difficulties. Feeding difficulties were present in 61 (53.5%) of the 114 children. The most common feeding difficulties were regular meal refusals (26.9%), extended mealtimes (26.7%), and problems with gagging on textured foods (26.5%). Most children (40/61) had ≥2 reported feeding difficulties, and eight had ≥4. Children with feeding difficulties had higher rates of constipation and vomiting: 60.7% (37/61) vs. 35.8% (19/53), p = 0.008 and 63.9% (39/61) vs. 41.5% (22/53), p = 0.017, respectively. Logistic regression analysis demonstrated an association between having feeding difficulties, the age of the child, and the initial symptom score. Gender and the number of foods excluded in the elimination diet were not significantly associated with feeding difficulties. This study found that feeding difficulties are common in children with non-IgE-mediated gastrointestinal allergies, but there is a paucity of food allergy specific tools for establishing feeding difficulties, which requires further research in the long-term and consensus in the short term amongst healthcare professions as to which tool is the best for food allergic children.


Assuntos
Hipersensibilidade Alimentar , Humanos , Pré-Escolar , Criança , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/epidemiologia , Masculino , Feminino , Adolescente , Lactente , Inquéritos e Questionários , Prevalência , Constipação Intestinal/epidemiologia , Constipação Intestinal/etiologia , Vômito/epidemiologia , Gastroenteropatias/epidemiologia
13.
Biology (Basel) ; 13(5)2024 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-38785838

RESUMO

Abiotic stress results in various physiological and biochemical changes in plants. Osmolytes play a pivotal role in improving the tolerance to abiotic stress in plants. This study evaluated the effectiveness of a commercial formulation, Carrabiitol®, an oligosaccharide polyol composition, in alleviating adverse impacts of abiotic stress in tomato (Solanum lycopersicum L. var. Arka Rakshak) plants. Plants were raised from seed and treated with 1 mL/L, 2 mL/L, and 3 mL/L of Carrabiitol®. The foliage of developing plants was treated at the 2-3 leaf stage (T2, T3, and T4) and at pre-flowering stage (T5, T6, and T7). Growth conditions were compared with those of plants developed from untreated seed (T1). Developing tomato plants were then exposed to flooding, salinity (50 mM NaCl), high temperature (41.1 °C), or drought at the flowering stage. Plants were evaluated for their dry weight, leaf water potential, stomatal conductance, transpiration rate, antioxidant potential, chlorophyll, carotenoid, glucose, sucrose, malondialdehyde, and proline contents. Pre-treated seed, which received a booster treatment at the 2-3 leaf stage (T4 = seed treatment and booster at the 2-3 leaf stage with 3 mL/L Carrabiitol®) and pre-flowering stages (T5, T6, and T7 = seed treatment and booster doses at the pre-flowering stage with 1, 2, and 3 mL/L Carrabiitol®, respectively), was effective in mitigating negative impacts on various growth parameters of stressed tomato plants (p < 0.05). Carrabiitol® may be an effective, sustainable, and bio-rational organic osmolyte formulation for reducing the effects of abiotic stress on plant growth and productivity.

14.
Eur Urol ; 86(2): 90-94, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38782695

RESUMO

Treatment options are limited for patients with non-clear cell renal cell carcinoma (nccRCC). Patients with nccRCC experienced a favorable objective response rate (ORR) in a phase 2 trial of cabozantinib plus nivolumab. We now report updated efficacy and safety results at median follow-up of 34 mo for patients with papillary, unclassified, or translocation-associated RCC. Cabozantinib and nivolumab were administered at standard doses to patients with metastatic nccRCC that had progressed on zero or one line of systemic therapy. The primary endpoint was the ORR according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Forty patients were treated. At median follow-up of 34 mo for survivors, the ORR was 48% (95% confidence interval [CI] 31.5-63.9%). Median PFS was 13 mo (95% CI 7-16); the 12-mo and 24-mo PFS rates were 51% (95% CI 34-65%) and 23% (95% CI 11-37%), respectively. Median OS was 28 mo (95% CI 23-43); the 18-mo and 36-mo OS rates were 70% (95% CI 53-82%) and 44% (95% CI 28-60%), respectively. No new safety signals were seen with cabozantinib and nivolumab. This extended follow-up analysis demonstrates promising efficacy, and highlights the potential for sustained responses with cabozantinib plus nivolumab in patients with metastatic nccRCC.


Assuntos
Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais , Neoplasias Renais , Nivolumabe , Piridinas , Humanos , Anilidas/uso terapêutico , Nivolumabe/uso terapêutico , Nivolumabe/efeitos adversos , Piridinas/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Intervalo Livre de Progressão , Resultado do Tratamento
15.
Clin Cancer Res ; 30(13): 2822-2834, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38652814

RESUMO

PURPOSE: Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood. EXPERIMENTAL DESIGN: Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays. RESULTS: Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo. CONCLUSIONS: Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.


Assuntos
Citocinas , Inibidores de Checkpoint Imunológico , Humanos , Masculino , Feminino , Inibidores de Checkpoint Imunológico/efeitos adversos , Pessoa de Meia-Idade , Idoso , Citocinas/metabolismo , Pele/patologia , Pele/imunologia , Pele/metabolismo , Pele/efeitos dos fármacos , Adulto , Toxidermias/etiologia , Toxidermias/patologia , Toxidermias/imunologia , Prurido/imunologia , Prurido/induzido quimicamente , Prurido/patologia , Prurido/etiologia , Prurido/genética , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Dermatopatias/induzido quimicamente , Dermatopatias/imunologia , Dermatopatias/patologia , Dermatopatias/etiologia , Exantema/induzido quimicamente , Exantema/patologia , Idoso de 80 Anos ou mais , Psoríase/tratamento farmacológico , Psoríase/imunologia , Psoríase/patologia , Psoríase/genética , Eczema/patologia , Eczema/tratamento farmacológico
16.
Blood ; 144(6): 639-645, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-38643492

RESUMO

ABSTRACT: Secondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia. The first 5 approved BCR::ABL1 TKIs target the adenosine triphosphate (ATP)-binding pocket. Mutations confer resistance to these ATP-competitive TKIs and those approved for other malignancies by decreasing TKI affinity and/or increasing ATP affinity. Asciminib, the first highly active allosteric TKI approved for any malignancy, targets an allosteric regulatory pocket in the BCR::ABL1 kinase C-lobe. As a non-ATP-competitive inhibitor, the activity of asciminib is predicted to be impervious to increases in ATP affinity. Here, we report several known mutations that confer resistance to ATP-competitive TKIs in the BCR::ABL1 kinase N-lobe that are distant from the asciminib binding pocket yet unexpectedly confer in vitro resistance to asciminib. Among these is BCR::ABL1 M244V, which confers clinical resistance even to escalated asciminib doses. We demonstrate that BCR::ABL1 M244V does not impair asciminib binding, thereby invoking a novel mechanism of resistance. Molecular dynamic simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the α-C helix as a mechanism of resistance. These N-lobe mutations may compromise the clinical activity of ongoing combination studies of asciminib with ATP-competitive TKIs.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/química , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Trifosfato de Adenosina/metabolismo , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-abl/química , Niacinamida/análogos & derivados , Pirazóis
18.
Cancer Res Commun ; 4(4): 1041-1049, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38592452

RESUMO

Cancer research is dependent on accurate and relevant information of patient's medical journey. Data in radiology reports are of extreme value but lack consistent structure for direct use in analytics. At Memorial Sloan Kettering Cancer Center (MSKCC), the radiology reports are curated using gold-standard approach of using human annotators. However, the manual process of curating large volume of retrospective data slows the pace of cancer research. Manual curation process is sensitive to volume of reports, number of data elements and nature of reports and demand appropriate skillset. In this work, we explore state of the art methods in artificial intelligence (AI) and implement end-to-end pipeline for fast and accurate annotation of radiology reports. Language models (LM) are trained using curated data by approaching curation as multiclass or multilabel classification problem. The classification tasks are to predict multiple imaging scan sites, presence of cancer and cancer status from the reports. The trained natural language processing (NLP) model classifiers achieve high weighted F1 score and accuracy. We propose and demonstrate the use of these models to assist in the manual curation process which results in higher accuracy and F1 score with lesser time and cost, thus improving efforts of cancer research. SIGNIFICANCE: Extraction of structured data in radiology for cancer research with manual process is laborious. Using AI for extraction of data elements is achieved using NLP models' assistance is faster and more accurate.


Assuntos
Trabalho de Parto , Neoplasias , Radiologia , Humanos , Gravidez , Feminino , Inteligência Artificial , Estudos Retrospectivos , Processamento de Linguagem Natural , Neoplasias/diagnóstico por imagem
19.
Eur J Orthop Surg Traumatol ; 34(4): 1939-1944, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38472434

RESUMO

PURPOSE: The number of patients with asymptomatic human immunodeficiency virus (AHIV) is increasing as the efficacy of antiretroviral therapy improves. While there is research on operative risks associated with having HIV, there is a lack of literature describing the impact of well-controlled HIV on postoperative complications. This study seeks to elucidate the impact of AHIV on postoperative outcomes after total hip (THA) and knee (TKA) arthroplasty. METHODS: The Nationwide Inpatient Sample was retrospectively reviewed for patients undergoing TKA and THA from 2005 to 2013. Subjects were subdivided into those with AHIV and those without HIV (non-HIV). Patient demographics, hospital-related parameters, and postoperative complications were all collected. One-to-one propensity score-matching, Chi-square analysis, and multivariate logistical regressions were performed to compare both cohorts. RESULTS: There were no significant differences between AHIV and non-HIV patients undergoing TKA or THA in terms of sex, age, insurance status, or total costs (all, p ≥ 0.081). AHIV patients had longer lengths of stay (4.0 days) than non-HIV patients after both TKA (3.3 days) and THA (3.1 days) (p ≤ 0.011). Both TKA groups had similar postoperative complication rates (p > 0.081). AHIV patients undergoing THA exhibited an increased rate of overall surgical complications compared non-HIV patients (0 vs. 4.5%, p = 0.043). AHIV was not associated with increased complications following both procedures. CONCLUSION: Despite lengthier hospital stays among AHIV patients, baseline AHIV was not associated with adverse outcomes following TKA and THA. This adds to the literature and warrants further research into the impact of asymptomatic, well-controlled HIV infection on postoperative outcomes following total joint arthroplasty.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Tempo de Internação , Complicações Pós-Operatórias , Pontuação de Propensão , Humanos , Masculino , Feminino , Artroplastia do Joelho/efeitos adversos , Artroplastia de Quadril/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Tempo de Internação/estatística & dados numéricos , Idoso , Infecções por HIV/complicações , Doenças Assintomáticas
20.
J Natl Compr Canc Netw ; 22(1): 43-69, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38394770

RESUMO

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Humanos , Crise Blástica/induzido quimicamente , Crise Blástica/tratamento farmacológico , Crise Blástica/genética , Inibidores de Proteínas Quinases/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Cromossomo Filadélfia , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Proteínas de Fusão bcr-abl/genética
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