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AIMS: Examine relationships between the systemic exposure of acalabrutinib, a highly selective, next-generation Bruton tyrosine kinase inhibitor, and its active metabolite (ACP-5862) vs. efficacy and safety responses in patients with B-cell malignancies who received acalabrutinib as monotherapy or in combination with obinutuzumab. METHODS: For exposure-efficacy analyses, patients with untreated chronic lymphocytic leukaemia were assessed for best overall response, progression-free survival and tumour regression. For exposure-safety analyses, incidences of grade ≥2 adverse events (AEs), grade ≥3 AEs and grade ≥2 events of clinical interest were assessed in patients with B-cell malignancies. Acalabrutinib and ACP-5862 pharmacokinetic (PK) parameter estimates were obtained from population PK modelling. Exposure calculations were based on study dosing regimens. Total active moieties were calculated to account for contributions of ACP-5862 to overall efficacy/safety. RESULTS: A total of 573 patients were included (exposure-efficacy analyses, n = 274; exposure-safety analyses, n = 573). Most patients (93%) received acalabrutinib 100 mg twice daily. Median total active area under the concentration-time curve (AUC24h,ss ) and total active maximal concentration at steady-state (Cmax,ss ) were similar for patients who received acalabrutinib as monotherapy or in combination with obinutuzumab, and for responders and nonresponders. No relationship was observed between AUC24h,ss /Cmax,ss and progression-free survival or tumour regression. Acalabrutinib AUC24h,ss and Cmax,ss were generally comparable across groups regardless of AE incidence. CONCLUSION: No clinically meaningful correlations between acalabrutinib PK exposure and efficacy and safety outcomes were observed. These data support the fixed acalabrutinib dose of 100 mg twice daily in the treatment of patients with B-cell malignancies.
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Leucemia Linfocítica Crônica de Células B , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , PirazinasRESUMO
BACKGROUND: Pseudoaneurysms of the foot are rare and can occur from a range of etiologies, including laceration from a foreign body. The majority of reported cases have been diagnosed by computed tomography, magnetic resonance imaging, or angiography. These tests require intravenous access and contrast, confer radiation, take time to perform and interpret, are expensive, and are not always readily available in the acute setting. No prior reported pseudoaneurysms of the foot have been diagnosed by point-of-care ultrasound (POCUS). CASE REPORT: An 8-year-old boy presented to the emergency department for evaluation of left foot pain and swelling 2 weeks after stepping on small pieces of broken glass. He had a 3 × 3 cm area of painful swelling and erythema at the medial plantar aspect of his foot. A cutaneous abscess was the working diagnosis and preparations were made for an incision and drainage procedure. However, POCUS revealed a medial plantar artery pseudoaneurysm. Incision and drainage would have led to unexpected arterial bleeding. Instead, the pediatric surgery service was consulted for pseudoaneurysm excision and arterial ligation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Incision of a pseudoaneurysm in the sole of the foot-thought to be an abscess based on clinical examination-would lead to unforeseen arterial bleeding. POCUS at the bedside can differentiate between simple abscess and pseudoaneurysm in order to guide appropriate and time-sensitive management. Historical and clinical clues to the diagnosis may include heavier-than-expected bleeding at the time of laceration and a pulsatile quality to the painful erythema and swelling.
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Falso Aneurisma , Pé , Sistemas Automatizados de Assistência Junto ao Leito , Ultrassonografia , Ferimentos Penetrantes , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/etiologia , Artérias/diagnóstico por imagem , Criança , Pé/irrigação sanguínea , Humanos , Masculino , Ferimentos Penetrantes/complicaçõesAssuntos
Antiasmáticos , Nebulizadores e Vaporizadores , Administração por Inalação , Criança , HumanosRESUMO
OBJECTIVE: In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain. METHODS: CSF-ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2-3 months), middle-aged (10-12 months), and old (18-20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence. RESULTS: Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-ß was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. INTERPRETATION: We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates.
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Envelhecimento/metabolismo , Encéfalo/metabolismo , Circulação Cerebrovascular/fisiologia , Taxa de Depuração Metabólica/fisiologia , Envelhecimento/patologia , Animais , Aquaporina 4/metabolismo , Encéfalo/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Neuroglia/metabolismo , Neuroglia/patologiaRESUMO
OBJECTIVE: This post hoc analysis evaluated romiplostim self-administration (SA group) vs. romiplostim administration by a healthcare provider in a clinical setting (HCP group) in patients with chronic immune thrombocytopenia (ITP). METHODS: Outcomes from 3 ITP trials allowing self-administration in patients achieving a stable romiplostim dose for ≥3 consecutive weeks were compared. Evaluations were conducted for 12-wk treatment intervals. Efficacy endpoints included percentage of patients and weeks with platelets within the target range of 50-200 × 10(9) /L and safety. RESULTS: Baseline characteristics suggested less severe disease in the SA groups (n = 563) than in the HCP groups (n = 241). The SA groups had greater proportions of patients achieving the target platelet range (55-58% vs. 40-52%) and greater proportions of weeks with a platelet response (75-88% vs. 47-76%) than the HCP groups. The rate of romiplostim discontinuation was twofold to fivefold lower in the SA groups than in the HCP groups. Rates of duration-adjusted adverse events (AEs), serious AEs and treatment-related AEs were also lower in the SA groups. CONCLUSIONS: In conclusion, in adults with ITP receiving romiplostim, self-administration was comparable to healthcare provider administration in terms of efficacy and safety profiles, suggesting that self-administration of romiplostim is a feasible option for certain patients with ITP.
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Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Doença Crônica , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Púrpura Trombocitopênica Idiopática/cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Fc/administração & dosagem , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Autoadministração , Trombopoetina/administração & dosagem , Trombopoetina/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVES: HIV-1 infection of the CNS is associated with impairment of CBF and neurocognitive function, and accelerated signs of aging. As normal aging is associated with rarefaction of the cerebral vasculature, we set out to examine chronic viral effects on the cerebral vasculature. METHODS: DOX-inducible HIV-1 Tat-tg and WT control mice were used. Animals were treated with DOX for three weeks or five to seven months. Cerebral vessel density and capillary segment length were determined from quantitative image analyses of sectioned cortical tissue. In addition, movement of red blood cells in individual capillaries was imaged in vivo using multiphoton microscopy, to determine RBCV and flux. RESULTS: Mean RBCV was not different between Tat-tg mice and age-matched WT controls. However, cortical capillaries from Tat-tg mice showed a significant loss of RBCV heterogeneity and increased RBCF that was attributed to a marked decrease in total cortical capillary length (35-40%) compared to WT mice. CONCLUSIONS: Cerebrovascular rarefaction is accelerated in HIV-1 Tat-transgenic mice, and this is associated with alterations in red cell blood velocity. These changes may have relevance to the pathogenesis of HIV-associated neurocognitive disorders in an aging HIV-positive population.
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Velocidade do Fluxo Sanguíneo , Genes tat , HIV-1/genética , Neocórtex/irrigação sanguínea , Produtos do Gene tat do Vírus da Imunodeficiência Humana/toxicidade , Animais , Astrócitos/metabolismo , Capilares/patologia , Doxiciclina/farmacologia , Índices de Eritrócitos , Hemodinâmica , Masculino , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência por Excitação Multifotônica , Neovascularização Fisiológica/efeitos dos fármacos , Células Piramidais/patologia , Proteínas Recombinantes de Fusão/toxicidade , Regulação para Cima/efeitos dos fármacos , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genéticaRESUMO
Cerebral cavernous malformation (CCM) has variable clinical symptoms, including potentially fatal hemorrhagic stroke. Treatment options are very limited, presenting a large unmet need. REC-994 (also known as tempol), identified as a potential treatment through an unbiased drug discovery platform, is hypothesized to treat CCMs through a reduction in superoxide, a reactive oxygen species. We investigated the safety, tolerability, and pharmacokinetic profile of REC-994 in healthy volunteers. Single- and multiple-ascending dose (SAD and MAD, respectively) studies were conducted in adult volunteers (ages 18-55). SAD study participants received an oral dose of REC-994 or placebo. MAD study participants were randomized 3:1 to oral doses of REC-994 or matching placebo, once daily for 10 days. Thirty-two healthy volunteers participated in the SAD study and 52 in the MAD study. Systemic exposure increased in proportion to REC-994 dose after single doses of 50-800 mg and after 10 days of dosing over the 16-fold dose range of 50-800 mg. Median Tmax and mean t1/2 were independent of dose in both studies, and the solution formulation was more rapidly absorbed. REC-994 was well tolerated. Treatment-emergent adverse effects across both studies were mild and transient and resolved by the end of the study. REC-994 has a favorable safety profile and was well tolerated in single and multiple doses up to 800 mg with no dose-limiting adverse effects identified. Data support conducting a phase 2 clinical trial in patients with symptomatic CCM.
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Óxidos N-Cíclicos , Relação Dose-Resposta a Droga , Marcadores de Spin , Humanos , Adulto , Masculino , Feminino , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/farmacocinética , Óxidos N-Cíclicos/efeitos adversos , Adulto Jovem , Pessoa de Meia-Idade , Adolescente , Método Duplo-Cego , Voluntários Saudáveis , Oxirredução , Administração Oral , Hemangioma Cavernoso do Sistema Nervoso Central/tratamento farmacológicoRESUMO
PURPOSE: Renal angioembolization (RAE) is widely employed in low-grade renal injuries and associated with improved patient outcomes, while surgery remains the mainstay for managing high-grade injuries. We compared the outcomes following surgery and RAE in high-grade renal trauma (HGRT). METHODS: We used the ACS TQIP 2016-2020 to identify patients ≥ 16 years with HGRT who underwent RAE or surgery. Morbidity was the primary outcome, while mortality and lengths of stay were secondary outcomes. We accounted for clinically relevant characteristics using multilevel logistic regression analyses. RESULTS: We included 591 patients, of whom 279 (47.2%) underwent RAE. After adjusting, there was no difference in morbidity, hospital LOS, or ICU LOS. The surgery cohort had increased odds of mortality (aOR 4.93; [95% CI] 1.53-15.82; p = 0.007) compared to RAE. In the penetrating injury subgroup, no associations between management and outcomes were observed. In the grade V injury subgroup, morbidity was significantly higher after surgery (aOR 4.64; [95% CI] 1.49-14.47; p = 0.008). CONCLUSION: Overall, RAE did not significantly impact morbidity but was associated with improved mortality. RAE could safeguard renal function by augmenting the efficacy of concurrent non-operative interventions. Randomized studies are needed to further validate the utility of RAE in HGRT.
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PURPOSE: Noncompressible truncal hemorrhage remains a leading cause of preventable death in the prehospital setting. Standardized and reproducible large animal models are essential to test new therapeutic strategies. However, existing injury models vary significantly in consistency and clinical accuracy. This study aims to develop a lethal porcine model to test hemostatic agents targeting noncompressible abdominal hemorrhages. METHODS: We developed a two-hit injury model in Yorkshire swine, consisting of a grade IV liver injury combined with hemodilution. The hemodilution was induced by controlled exsanguination of 30% of the total blood volume and a 3:1 resuscitation with crystalloids. Subsequently, a grade IV liver injury was performed by sharp transection of both median lobes of the liver, resulting in major bleeding and severe hypotension. The abdominal incision was closed within 60 s from the injury. The endpoints included mortality, survival time, serum lab values, and blood loss within the abdomen. RESULTS: This model was lethal in all animals (5/5), with a mean survival time of 24.4 ± 3.8 min. The standardized liver resection was uniform at 14.4 ± 2.1% of the total liver weight. Following the injury, the MAP dropped by 27 ± 8mmHg within the first 10 min. The use of a mixed injury model (i.e., open injury, closed hemorrhage) was instrumental in creating a standardized injury while allowing for a clinically significant hemorrhage. CONCLUSION: This novel highly lethal, consistent, and clinically relevant translational model can be used to test and develop life-saving interventions for massive noncompressible abdominal hemorrhage.
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Colloidal CdS quantum dots (QDs) were synthesized with tunable surface composition. Surface stoichiometry was controlled by applying reactive secondary phosphine sulfide precursors in a layer-by-layer approach. The surface composition was observed to greatly affect photoluminescence properties. Band edge emission was quenched in sulfur terminated CdS QDs and fully recovered when QDs were cadmium terminated. Calculations suggest that electronic states inside the band gap arising from surface sulfur atoms could trap charges, thus inhibiting radiative recombination and facilitating nonradiative relaxation.
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Compostos de Cádmio/química , Coloides/química , Cristalização/métodos , Pontos Quânticos , Compostos de Selênio/química , Substâncias Macromoleculares/química , Teste de Materiais , Conformação Molecular , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
PROBLEM: Mental health conditions are common among medical students. While stigma contributes to low rates of help seeking, little programming exists to address stigma. APPROACH: In 2015, the authors developed a mental health initiative (MHI) to combat stigma at the Pritzker School of Medicine featuring 3 elements: (1) Mental Health Panel, an annual first-year event where faculty/peers share mental health stories; (2) Pritzker, I Screwed Up, an annual all-school event where faculty/peers share experiences with failure; and (3) Humans of Pritzker, a social media initiative featuring students' mental health posts. Postevent surveys and the 2021-2022 MHI survey assessed student satisfaction and impact on stigma and help-seeking behaviors. Student Counseling Services utilization rates for medical and nonmedical students were compared for academic years 2014-2015 vs 2018-2019 and 2020-2021 to account for the pandemic's impact on mental health care utilization. OUTCOMES: The MHI survey response rate was 61% (261/430). Respondents were distributed across class-years. Most were female (57%, 150/261). The majority agreed they could speak about mental health without judgment from peers (78%, 203/259) and faculty (57%, 149/260). Most (62%, 161/260) utilized mental health services during medical school. Of these, 41% (66/161) agreed that MHI programming contributed to their decision to seek care. On the 2021-2022 Mental Health Panel and Pritzker, I Screwed Up evaluations, almost all agreed that faculty/peers sharing experiences destigmatized mental illness (99%, 78/79) and making mistakes (96%, 152/159). Student Counseling Services utilization increased from 8% (32/389) for 2014-2015 to 19% (75/394) for 2018-2019 and 33% (136/406) for 2020-2021 for medical students, compared with 19% (2,248/12,138) to 21% (3,024/14,293) and 22% (3,285/15,004) for nonmedical students. NEXT STEPS: Faculty and peers sharing mental health stories may help reduce stigma and increase help seeking in medical students. Future work should explore the longitudinal impact of programming and disseminating similar initiatives at other institutions.
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Transtornos Mentais , Serviços de Saúde Mental , Estudantes de Medicina , Humanos , Feminino , Masculino , Saúde Mental , Estudantes de Medicina/psicologia , Transtornos Mentais/terapia , Transtornos Mentais/psicologia , Estigma Social , Aceitação pelo Paciente de Cuidados de Saúde/psicologiaRESUMO
Uterine leiomyomas cause heavy menstrual bleeding, anemia, and pregnancy loss in millions of women worldwide. Driver mutations in the transcriptional mediator complex subunit 12 (MED12) gene in uterine myometrial cells initiate 70% of leiomyomas that grow in a progesterone-dependent manner. We showed a distinct chromatin occupancy landscape of MED12 in mutant MED12 (mut-MED12) versus WT-MED12 leiomyomas. Integration of cistromic and transcriptomics data identified tryptophan 2,3-dioxygenase (TDO2) as the top mut-MED12 target gene that was significantly upregulated in mut-MED12 leiomyomas when compared with adjacent myometrium and WT-MED12 leiomyomas. TDO2 catalyzes the conversion of tryptophan to kynurenine, an aryl hydrocarbon receptor (AHR) ligand that we confirmed to be significantly elevated in mut-MED12 leiomyomas. Treatment of primary mut-MED12 leiomyoma cells with tryptophan or kynurenine stimulated AHR nuclear translocation, increased proliferation, inhibited apoptosis, and induced AHR-target gene expression, whereas blocking the TDO2/kynurenine/AHR pathway by siRNA or pharmacological treatment abolished these effects. Progesterone receptors regulated the expression of AHR and its target genes. In vivo, TDO2 expression positively correlated with the expression of genes crucial for leiomyoma growth. In summary, activation of the TDO2/kynurenine/AHR pathway selectively in mut-MED12 leiomyomas promoted tumor growth and may inform the future development of targeted treatments and precision medicine.
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Leiomioma , Neoplasias Uterinas , Feminino , Humanos , Triptofano , Cinurenina/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Triptofano Oxigenase/genética , Triptofano Oxigenase/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Leiomioma/genética , Leiomioma/metabolismo , Leiomioma/patologia , Mutação , Complexo Mediador/genética , Complexo Mediador/metabolismoRESUMO
Aim: Healthcare utilization and costs were compared following 25-gene panel (panel) or single syndrome (SS) testing for hereditary breast and ovarian cancer. Materials & methods: Retrospective cohort study of patients unaffected by cancer with panel (n = 6359) or SS (n = 4681) testing for hereditary breast and ovarian cancer (01 January 2014 to 31 December 2016). Groups were determined by test type and result (positive, negative, variant of uncertain significance [VUS]). Results: There were no differences in total unadjusted healthcare costs between the panel (US$14,425) and SS (US$14,384) groups (p = 0.942). Among VUS patients in the panel and SS groups, mean all-cause costs were US$14,404 versus US$20,607 (p = 0.361) and mean risk-reduction/early detection-specific costs were US$718 versus US$679 (p = 0.890), respectively. Adjusted medical costs were not significantly different between panel and SS cohorts. Conclusion: Healthcare utilization and costs were comparable between the SS and panel tests overall and for patients with VUS.
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Neoplasias da Mama , Neoplasias Ovarianas , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Carcinoma Epitelial do Ovário , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Estudos RetrospectivosRESUMO
Asian American medical students (AAMSs) face significant bias in the medical learning environment and are more likely than White students to perceive their school climate negatively. Little is known about the factors that contribute to AAMSs' negative experiences. This perspective aims to describe AAMSs' experiences with diversity and inclusion efforts using survey data from a midwest regional conference, Asians in Medicine: A Conference on Advocacy and Allyship. AAMS respondents reported feeling excluded from diversity and inclusion efforts and conference participants advocated for institutional culture and climate assessments stratified by race and disaggregated into Asian subgroups.
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Somatic mutations are rare in pediatric acute myeloid leukemia (pAML), indicating that alternate strategies are needed to identify targetable dependencies. We performed the first enhancer mapping of pAML in 22 patient samples. Generally, pAML samples were distinct from adult AML samples, and MLL (KMT2A)-rearranged samples were also distinct from non-KMT2A-rearranged samples. Focusing specifically on superenhancers (SEs), we identified SEs associated with many known leukemia regulators. The retinoic acid receptor alpha (RARA) gene was differentially regulated in our cohort, and a RARA-associated SE was detected in 64% of the study cohort across all cytogenetic and molecular subtypes tested. RARA SE+ pAML cell lines and samples exhibited high RARA messenger RNA levels. These samples were specifically sensitive to the synthetic RARA agonist tamibarotene in vitro, with slowed proliferation, apoptosis induction, differentiation, and upregulated retinoid target gene expression, compared with RARA SE- samples. Tamibarotene prolonged survival and suppressed the leukemia burden of an RARA SE+ pAML patient-derived xenograft mouse model compared with a RARA SE- patient-derived xenograft. Our work shows that examining chromatin regulation can identify new, druggable dependencies in pAML and provides a rationale for a pediatric tamibarotene trial in children with RARA-high AML.
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Leucemia Mieloide Aguda , Animais , Criança , Estudos de Coortes , Regulação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , CamundongosRESUMO
BACKGROUND: Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. METHODS: This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. FINDINGS: Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). INTERPRETATION: This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. FUNDING: Acerta Pharma.
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Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Proteínas de Neoplasias/antagonistas & inibidores , Neutropenia/induzido quimicamente , Dor/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Qualidade de Vida , Recidiva , Infecções Respiratórias/etiologia , Terapia de Salvação , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/enzimologia , Macroglobulinemia de Waldenstrom/genéticaRESUMO
The tight coupling between cerebral blood flow and neural activity is a key feature of normal brain function and forms the basis of functional hyperemia. The mechanisms coupling neural activity to vascular responses, however, remain elusive despite decades of research. Recent studies have shown that cerebral functional hyperemia begins in capillaries, and red blood cells (RBCs) act as autonomous regulators of brain capillary perfusion. RBCs then respond to local changes of oxygen tension (PO2) and regulate their capillary velocity. Using ex vivo microfluidics and in vivo two-photon microscopy, we examined RBC capillary velocity as a function of PO2 and showed that deoxygenated hemoglobin and band 3 interactions on RBC membrane are the molecular switch that responds to local PO2 changes and controls RBC capillary velocity. Capillary hyperemia can be controlled by manipulating RBC properties independent of the neurovascular unit, providing an effective strategy to treat or prevent impaired functional hyperemia.
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Encéfalo/irrigação sanguínea , Membrana Eritrocítica/fisiologia , Hiperemia/sangue , Oxigênio/sangue , Animais , Proteína 1 de Troca de Ânion do Eritrócito/genética , Proteína 1 de Troca de Ânion do Eritrócito/metabolismo , Velocidade do Fluxo Sanguíneo/fisiologia , Circulação Cerebrovascular , Hemoglobinas/química , Hemoglobinas/metabolismo , Humanos , Hiperemia/fisiopatologia , Dispositivos Lab-On-A-Chip , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
In many clinical studies, patients may experience the same type of event of interest repeatedly over time. However, the assessment of treatment effects is often complicated by the rescue medication uses due to ethical reasons. For example, in the motivating trial in studying the Immune Thrombocytopenia (ITP), when the interest lies in evaluating the treatment benefit of investigational product (IP) on reducing patient's repeated bleeding, rescue medication such as platelet transfusions may be allowed to raise platelet counts. Both the intention-to-treat analysis and treating the intermediate rescue medication as covariate tend to attenuate the treatment benefit, and the estimates can be biased if interpreted as causal. In this paper, we propose a general causal framework when intermediate rescue medications are informative. We adopt the inverse weighted estimation approach to estimate the treatment effect, where weights are constructed to reflect time-dependent medication use probabilities. The proposed estimators are shown to be asymptotically normal and are demonstrated to perform well in small-sample simulation studies. The application to the ITP studies reveals a stronger benefit of using IP in reducing bleeding.